Therapeutic compounds and methods of use thereof

ABSTRACT

The invention provides compounds having the general Formula (I);and pharmaceutically acceptable salts thereof; wherein the variables RA, RAA, subscript n, subscript q, ring A, X2, L, subscript m, X1, R1, R2, R3, R4, R5, D and E have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/150,070, filed 2 Oct. 2018, which is a divisional of U.S. applicationSer. No. 15/988,956, filed 24 May 2018, now U.S. Pat. No. 10,125,098,issued 13 Oct. 2018, which is a divisional of U.S. application Ser. No.15/321,335, filed 22 Dec. 2016, now U.S. Pat. No. 10,005,724, issued 26Jun. 2018, which is a 35 U.S.C. § 371 application of InternationalApplication No. PCT/US2015/039413, filed on 7 Jul. 2015, which claimspriority to U.S. Provisional Application No. 62/021,587 filed on 7 Jul.2014. The entire contents of the foregoing are incorporated herein byreference.

The present invention relates to organic compounds useful for therapy ina mammal, and in particular to inhibitors of sodium channel (e.g.,NaV1.7) that are useful for treating sodium channel-mediated diseases orconditions, such as pain, as well as other diseases and conditionsassociated with the modulation of sodium channels.

Voltage-gated sodium channels are transmembrane proteins that initiateaction potentials in nerve, muscle and other electrically excitablecells, and are a necessary component of normal sensation, emotions,thoughts and movements (Catterall, W. A., Nature (2001). Vol. 409, pp.988-990). These channels consist of a highly processed alpha subunitthat is associated with auxiliary beta subunits. The pore-forming alphasubunit is sufficient for channel function, but the kinetics and voltagedependence of channel gating are in part modified by the beta subunits(Goldin et al., Neuron (2000), Vol. 28, pp. 365-368).Electrophysiological recording, biochemical purification, and molecularcloning have identified ten different sodium channel alpha subunits andfour beta subunits (Yu, F. H., et al., Sci. STKE (2004), 253; and Yu, F.H., et al., Neurosci. (2003), 20:7577-85).

The sodium channel family of proteins has been extensively studied andshown to be involved in a number of vital body functions. Research inthis area has identified variants of the alpha subunits that result inmajor changes in channel function and activities, which can ultimatelylead to major pathophysiological conditions. The members of this familyof proteins are denoted NaV1.1 to NaV1.9.

NaV1.7 is a tetrodotoxin-sensitive voltage-gated sodium channel encodedby the gene SCN9A. Human NaV1.7 was first cloned from neuroendocrinecells (Klugbauer, N., et al., 1995 EMBO J., 14 (6): 1084-90.) and ratNaV1.7 was cloned from a pheochromocytoma PC12 cell line (Toledo-Aral,J. J., et al., Proc. Natl. Acad. Sci. USA (1997), 94:1527-1532) and fromrat dorsal root ganglia (Sangameswaran, L., et al., (1997). J. Biol.Chem., 272 (23): 14805-9). NaV1.7 is expressed primarily in theperipheral nervous system, especially nocieptors and olfactory neuronsand sympathetic neurons. The inhibition, or blocking, of NaV1.7 has beenshown to result in analgesic activity. Knockout of NaV1.7 expression ina subset of sensory neurons that are predominantly nociceptive resultsin resistance to inflammatory pain (Nassar, et al., op. cit.). Likewise,loss of function mutations in humans results in congenital indifferenceto pain (CIP), in which the individuals are resistant to bothinflammatory and neuropathic pain (Cox, J. J., et al., Nature (2006):444:894-898; Goldberg, Y. P., et al., Clin. Genet. (2007); 71:311-319).Conversely, gain of function mutations in NaV1.7 have been establishedin two human heritable pain conditions, primary erythromelalgia andfamilial rectal pain, (Yang, Y., et al., J. Med. Genet. (2004), 41(3):171-4). In addition, a single nucleotide polymorphism (R1150W) that hasvery subtle effects on the time- and voltage-dependence of channelgating has large effects on pain perception (Estacion, M., et al., 2009.Ann Neurol 66: 862-6; Reimann, F., et al., Proc Natl Acad Sci USA(2010), 107: 5148-53). About 10% of the patients with a variety of painconditions have the allele conferring greater sensitivity to pain andthus might be more likely to respond to block of NaV1.7. Because NaV1.7is expressed in both sensory and sympathetic neurons, one might expectthat enhanced pain perception would be accompanied by cardiovascularabnormalities such as hypertension, but no correlation has beenreported. Thus, both the CIP mutations and SNP analysis suggest thathuman pain responses are more sensitive to changes in NaV1.7 currentsthan are perturbations of autonomic function.

Sodium channel blockers have been shown to be useful in the treatment ofpain, (see, e.g., Wood, J. N., et al., J. Neurobiol. (2004), 61(1),55-71. Genetic and functional studies have provided evidence to supportthat activity of NaV1.7 as a major contributor to pain signalling inmammals. (See Hajj, et al. Nature Reviews Neuroscience; 2013, vol 14,49-62; and Lee, et al. Cell; 2014, vol 157: 1-12). Presently, there area limited number of effective sodium channel blockers for the treatmentof pain with a minimum of adverse side effects which are currently inthe clinic. Thus there remains a need for selective voltage-gated sodiumchannel modulators (e.g., modulators of NaV1.7) that can provide agreater therapeutic index for treatment.

SUMMARY OF THE INVENTION

In one aspect the present invention provides novel compounds havingsodium channel blocking activity that are useful for the treatment ofpain. In a first embodiment (Embodiment 1; abbreviated as “E1”) theinvention provides for a compound of Formula (I):

or a pharmaceutically acceptable salt thereof; wherein:D is absent or is —CH₂—;E is tetrazolyl, —C(═O)OR^(o), or —C(═O)NR^(oa)R^(ob),R^(o) is hydrogen or C₁₋₆ alkyl;R^(oo) is hydrogen or C₁₋₆ alkyl;R^(ob) is hydrogen, hydroxyl, or C₁₋₆ alkyl;R¹ and R² are each independently selected from the group consisting ofhydrogen, —CN, —F, —Cl, —Br, —I, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈heteroalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, C₂₋₇ heterocycloalkyl-C₁₋₆alkyl, C₃₋₈ cycloalkyl, and C₂₋₇ heterocycloalkyl, wherein said R¹ andR² substituents are independently optionally substituted with 1-3R^(1/2) substituents selected from the group consisting of F, Cl, Br, I,—CN, —OH, —NH₂, —NO₂, carboxy, C₁₋₆ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy,C₁₋₈ alkylthio, C₁₋₈ alkylamino and C₁₋₈ dialkylamino;or R¹ and R² are combined to form a 3- to 7-membered carbocycle orheterocycle ring comprising 1 to 2 heteroatoms selected from N, O and S,and wherein said carbocycle or heterocycle ring are optionallysubstituted with 1 to 3 R^(1/2) substituents selected from the groupconsisting of F, Cl, Br, I, —CN, —OH, —NH₂, —NO₂, ═CH—R^(1/2a), C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈ alkylthio, C₁₋₈ alkylamino andC₁₋₈ dialkylamino, wherein said R^(1/2a) is H or C₁₋₈ alkyl;or R¹ and R⁴ are combined to form a 3- to 7-membered heterocycle ringcomprising 1 to 2 heteroatoms selected from N, O and S, wherein saidheterocycle ring is optionally substituted with 1 to 3 R^(1/4)substituents selected from the group consisting of F, Cl, Br, I, —CN,—OH, —NH₂, —NO₂, ═CH—R^(1/4a), C₁₋₆ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy,C₁₋₈ alkylthio, C₁₋₈ alkylamino and C₁₋₈ dialkylamino, wherein saidR^(1/4a) is H or C₁₋₈ alkyl; and R² is selected from the groupconsisting of hydrogen, —CN, —F, —Cl, —Br, —I, C₁₋₈ alkyl, C₁₋₈haloalkyl and C₁₋₈ heteroalkyl;R³ is selected from the group consisting of hydrogen, F, Cl, Br, I, —CN,C₁₋₈ alkyl and C₁₋₈ haloalkyl;R⁴ is selected from the group consisting of hydrogen, C₁₋₄ alkyl andC₁₋₄ haloalkyl; or R¹ and R⁴ are combined to form a 3- to 7-memberedheterocycle ring as described above;R⁵ is selected from the group consisting of F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl and C₂₋₇heterocyclyl, wherein said C₃₋₈ cycloalkyl and C₂₋₇ heterocyclyl isoptionally substituted with 1-3 substituents selected from F, Cl, Br, I,—OH, —NH₂, —NH(C₁₋₄ alkyl)-, —N(C₁₋₄ dialkyl)-, and C₁₋₄ alkylsubstituted with 1-3 substituents selected from F, Cl, Br, I, —OH, —NH₂,—NH(C₁₋₄ alkyl)- and —N(C₁₋₄ dialkyl)-;L is C₁₋₆ alkylene, wherein L is optionally substituted with from 1 to 3substituents selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, halo, oxo (═O), and C₁₋₄ haloalkyl, and wherein any twosubstituents attached to the same atom on L are optionally combined toform a 3- to 5-membered carbocyclic ring;the subscript m represents the integer 0 or 1;X¹ and X² are each independently selected from the group consisting ofabsent, —S—, —O— and —N(R^(X))— wherein R^(x) is H, C₁₋₈ alkyl, C₁₋₈haloalkyl, and wherein if the subscript m is 0 then one of X¹ or X² isabsent;the ring “A” in is selected from the group consisting of:(i) C₂₋₁₁ heterocycle comprising a nitrogen atom and further optionallycomprising 1-2 heteroatoms selected from N, O and S; wherein

-   -   R^(AA) is independently selected from the group consisting of        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ heteroalkyl, F, Cl, Br, I, —CN,        —(X^(RAA))₀₋₁NR_(AA1)R^(AA2), —(X^(RAA))₀₋₁OR^(AA1),        —(X^(RAA))₀₋₁SR^(AA1), —(X^(RAA))₀₋₁N(R^(AA1))C(═O)OR^(AA3),        —(X^(RAA))₀₋₁OC(═O)N(R^(AA1))(R^(AA2)),        —(X^(RAA))₀₋₁N(R^(AA1))C(═O)N(R^(AA1))(R^(AA2)),        —(X^(RAA))₀₋₁C(═O)N(R^(AA1))(R^(AA2)),        —(X^(RAA))₀₋₁N(R^(AA1))C(═O)R^(AA2), —(X^(RAA))₀₋₁C(═O)OR^(AA1),        —(X^(RAA))₀₋₁OC(═O)R^(AA1), —(X^(RAA))₀₋₁S(O)₁₋₂R^(AA3),        —(X^(RAA))₀₋₁S(O)₁₋₂N(R^(AA1))(R^(AA2)),        —(X^(RAA))₀₋₁N(R^(AA1))S(O)₁₋₂N(R^(AA1))(R^(AA2)),        —(X^(RAA))₀₋₁N(R^(AA1))S(O)₁₋₂(R^(AA3)), and —C(═O)R^(AA1);        wherein X^(RAA) is selected from the group consisting of absent,        C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄        alkynylene; X^(RAA) is optionally substituted with 1 to 3        substituents selected from the group consisting of C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ heteroalkyl and oxo (═O); R^(AA1) and        R^(M2) are each independently selected from the group consisting        of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl and C₁₋₈ haloalkyl;        R^(AA3) is selected from the group consisting of C₁₋₈ alkyl,        C₂₋₈ alkenyl and C₁₋₈ haloalkyl; wherein R^(AA) substituent is        optionally substituted with from 1 to 5 R^(RAA) substituents        selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino and C₁₋₄        dialkylamino;    -   n is an integer from 0 to 5;    -   R^(A) is selected from the group consisting of —(C═O)OR^(A1),        (C₆₋₁₀ aryl)₁₋₂-(X^(RA))—, (5- to 10-membered        heteroaryl)₁₋₂-(X^(RA))—, (C₃₋₁₂ cycloalkyl)₁₋₂-(X^(RA))—, and        (C₂₋₁₁ heterocyclyl)₁₋₂-(X^(RA))—, wherein said C₆₋₁₀ aryl, 5-        to 10 membered heteroaryl, C₃₋₁₂ cycloalkyl and C₂₋₁₁        heterocyclyl of R^(A) is independently optionally substituted        with from 1 to 5 R^(RA) substituents selected from the group        consisting of F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄        dialkylamino, —N(R^(A1))C(═O)OR^(A3), —OC(═O)N(R^(A1))(R^(A2)),        —N(R^(A1)), —N(R^(A1))C(═O)N(R^(A1))(R^(A2)),        —C(═O)N(R^(A1))(R^(A2)), —N(R^(A1))C(═O)R^(A2), —C(═O)OR^(A1),        —C(═O)OR^(A1), —OC(═O)R^(A1), —S(O)₁₋₂R^(A3),        —S(O)₁₋₂N(R^(A1))(R^(A2)), —N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)),        —N(R^(A1))S(O)₁₋₂(R^(A3)), —C(═O)R^(A1), C₃₋₆ cycloalkyl, C₃₋₆        cycloalkoxy, C₂₋₅ heterocyclyl, C₂₋₅ heterocyclyloxy, 5- to 6        membered heteroaryl and phenyl, wherein the R^(RA) substituent        is optionally substituted with 1 to 5 R^(RAi) substituents        selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄(halo)alkoxy, C₁₋₄ alkylamino        and C₁₋₄ dialkylamino; X^(RA) is selected from the group        consisting of absent, —O—, —S—, —N(H)—, —N(C₁₋₄ alkyl)-,        —S(O)₁₋₂—, —S(O)₁₋₂N(H)—, —C(C═O)N(H)—, —C(C═O)N(C₁₋₄ alkyl)-,        —OC(C═O)N(H)—, —N(H)C(C═O)N(H)—, —N(H)S(O)₁₋₂N(H)—, —C(═O)—,        C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄        alkynylene; wherein X^(RA) is optionally substituted with 1 to 3        substituents selected from the group consisting of C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ heteroalkyl and oxo (═O); R^(A1) and R^(A2)        are each independently selected from the group consisting of        hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈        cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl and C₂₋₇        heterocyclyl; R^(A3) is selected from the group consisting of        C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl,        phenyl, benzyl, 5- to 6-membered heteroaryl and C₂₋₇        heterocyclyl; and    -   q is an integer from 0 to 1;        (ii) C₃₋₁₂ membered carbocycle; wherein    -   R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈        alkoxy, C₁₋₈ alkylamino, C₁₋₈ dialkylamino, C₁₋₈ haloalkyl, F,        Cl, Br, I, —OH, —CN, —NO₂, ═O, —(X^(RA))₀₋₁NR^(A1)R^(A2),        —(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1),        —(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3),        —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2), —(X^(RA))₀₋₁C(═O)OR^(A1),        —(X^(RA))₀₋₁OC(═O)R^(A1), —(X^(RA))₀₋₁S(O)₁₋₂(R^(A3)),        —(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), —C(═O)R^(A1), C₃₋₆        cycloalkyl, C₂₋₅ heterocyclyl, 5- to 10 membered heteroaryl and        phenyl; wherein X^(RA) is selected from the group consisting of        C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄        alkynylene; wherein R^(A1) and R^(A2) are independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, 5- to 6        membered heteroaryl and C₂₋₇ heterocyclyl; R^(A3) is selected        from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈        cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl and C₂₋₇        heterocyclyl; wherein R^(A) substituent is optionally        substituted with from 1 to 5 R^(RA) substituents selected from,        F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino and C₁₋₄ dialkylamino;    -   n is the integer 0; and    -   q is the integer 0 to 6;        (iii) phenyl substituted at the 2-position, the 3,4-positions,        the 2,4-positions, or the 3,5-positions with groups        independently selected from R^(A), wherein each    -   R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈        alkoxy, C₁₋₈ alkylamino, C₁₋₈ dialkylamino, C₁₋₈ haloalkyl, F,        Cl, Br, I, —OH, —CN, —NO₂, ═O, —(X^(RA))₀₋₁NR^(A1)R^(A2),        —(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1),        —(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3),        —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2), —(X^(RA))₀₋₁C(═O)OR^(A1),        —(X^(RA))₀₋₁OC(═O)R^(A1), —(X^(RA))₀₋₁S(O)₁₋₂(R^(A3)),        —(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), —C(═O)R^(A1), C₃₋₆        cycloalkyl, C₃₋₆ cycloalkoxy, C₂₋₅ heterocyclyl, C₂₋₅        heterocycloalkoxy, 5- to 10 membered heteroaryl and phenyl;        wherein X^(RA) is selected from the group consisting of C₁₋₄        alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄        alkynylene; wherein R^(A1) and R^(A2) are independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, 5- to        6-membered heteroaryl and C₂₋₇ heterocyclyl; R^(A3) is selected        from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈        cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl and C₂₋₇        heterocyclyl; wherein R^(A) substituent is optionally        substituted with from 1 to 5 R^(RA) substituents selected from,        F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, C₂₋₅        heterocyclyloxy, and C₂₋₇ heterocyclyl that is optionally        substituted with one or more substituents independently selected        from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ alkoxy carbonyl;        (iv) naphthyl; and (v) 5- to 10-membered heteroaryl comprising        1- to 3-nitrogen atoms and optionally further comprising 1- to        2-heteroatoms selected from O and S; wherein in (iv) and (v)    -   R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈        alkoxy, C₁₋₈ alkylamino, C₁₋₈ dialkylamino, C₁₋₈ haloalkyl, F,        Cl, Br, I, —OH, —CN, —NO₂, ═O, —(X^(RA))₀₋₁NR^(A1)R^(A2),        —(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1),        —(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3),        —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2), —(X^(RA))₀₋₁C(═O)OR^(A1),        —(X^(RA))₀₋₁OC(═O)R^(A1), —(X^(RA))₀₋₁S(O)₁₋₂(R^(A3)),        —(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), —C(═O)R^(A1), C₃₋₆        cycloalkyl, C₂₋₅ heterocyclyl, 5- to 10 membered heteroaryl and        phenyl; wherein X^(RA) is selected from the group consisting of        C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄        alkynylene; wherein R^(A1) and R^(A2) are independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, 5- to 6        membered heteroaryl and C₂₋₇ heterocyclyl; R^(A3) is selected        from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈        cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl and C₂₋₇        heterocyclyl; wherein R^(A) substituent is optionally        substituted with from 1 to 5 R^(RA) substituents selected from,        F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄alkyl,        C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄ dialkylamino        and C₂₋₅ heterocyclyloxy;    -   n is the integer 0; and    -   q is an integer from 0 to 4.

Further embodiments (E2-E52) of the first embodiment of compounds of theinvention are described below.

E2 The compound of E1 which is a compound of Formula (II):

or a pharmaceutically acceptable salt thereof; wherein:R^(o) is hydrogen or C₁₋₆ alkyl;R¹ and R² are each independently selected from the group consisting ofhydrogen, —CN, —F, —Cl, —Br, —I, C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈heteroalkyl, C₃₋₈ cycloalkyl-C₁₋₆ alkyl, C₂₋₇ heterocycloalkyl-C₁₋₆alkyl, wherein said R¹ and R² substituents are independently optionallysubstituted with 1-3 R^(1/2) substituents selected from the groupconsisting of F, Cl, Br, I, —CN, —OH, —NH₂, —NO₂, carboxy, C₁₋₆ alkyl,C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈ alkylthio, C₁₋₈ alkylamino and C₁₋₈dialkylamino;or R¹ and R² are combined to form a 3- to 7-membered carbocycle orheterocycle ring comprising 1 to 2 heteroatoms selected from N, O and S,and wherein said carbocycle or heterocycle ring are optionallysubstituted with 1 to 3 R^(1/2) substituents selected from the groupconsisting of F, Cl, Br, I, —CN, —OH, —NH₂, —NO₂, C₁₋₆ alkyl, C₁₋₈haloalkyl, C₁₋₈ alkoxy, C₁₋₈ alkylthio, C₁₋₈ alkylamino and C₁₋₈dialkylamino;or R¹ and R⁴ are combined to form a 3- to 7-membered heterocycle ringcomprising 1 to 2 heteroatoms selected from N, O and S, wherein saidheterocycle ring is optionally substituted with 1 to 3 R^(1/4)substituents selected from the group consisting of F, Cl, Br, I, —CN,—OH, —NH₂, —NO₂, C₁₋₆ alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₁₋₈alkylthio, C₁₋₈ alkylamino and C₁₋₈ dialkylamino; and R² is selectedfrom the group consisting of hydrogen, —CN, —F, —Cl, —Br, —I, C₁₋₈alkyl, C₁₋₈ haloalkyl and C₁₋₈ heteroalkyl;R³ is selected from the group consisting of hydrogen, F, Cl, Br, I, —CN,C₁₋₈ alkyl and C₁₋₈ haloalkyl;R⁴ is selected from the group consisting of hydrogen, C₁₋₄ alkyl andC₁₋₄ haloalkyl; or R¹ and R⁴ are combined to form a 3- to 7-memberedheterocycle ring as described above;R⁵ is selected from the group consisting of F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₈ cycloalkyl and C₂₋₇heterocyclyl, wherein said C₃₋₈ cycloalkyl and C₂₋₇ heterocyclyl isoptionally substituted with 1-3 substituents selected from F, Cl, Br, I,—OH, —NH₂, —NH(C₁₋₄ alkyl)-, —N(C₁₋₄ dialkyl)-, and C₁₋₄ alkylsubstituted with 1-3 substituents selected from F, Cl, Br, I, —OH, —NH₂,—NH(C₁₋₄ alkyl)- and —N(C₁₋₄ dialkyl)-;L is C₁₋₆ alkylene, wherein L is optionally substituted with from 1 to 3substituents selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, halo, oxo (═O), and C₁₋₄ haloalkyl, and wherein any twosubstituents attached to the same atom on L are optionally combined toform a 3- to 5-membered carbocyclic ring;the subscript m represents the integer 0 or 1;X¹ and X² are each independently selected from the group consisting ofabsent, —S—, —O— and —N(R^(X))— wherein R^(x) is H, C₁₋₈ alkyl, C₁₋₈haloalkyl, and wherein if the subscript m is 0 then one of X¹ or X² isabsent;the ring “A” in is selected from the group consisting of:(i) C₂₋₁₁ heterocycle comprising a nitrogen atom and further optionallycomprising 1-2 heteroatoms selected from N, O and S; wherein

-   -   R^(AA) is independently selected from the group consisting of        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ heteroalkyl, F, Cl, Br, I, —CN,        —(X^(RAA))₀₋₁NR_(AA1)R^(AA2), —(X^(RAA))₀₋₁OR^(AA1),        —(X^(RAA))₀₋₁SR^(AA1), —(X^(RAA))₀₋₁N(R^(AA1))C(═O)OR^(AA3),        —(X^(RAA))₀₋₁OC(═O)N(R^(AA1))(R^(AA2)),        —(X^(RAA))₀₋₁N(R^(AA1))C(═O)N(R^(AA1))(R^(AA2)),        —(X^(RAA))₀₋₁C(═O)N(R^(AA1))(R^(AA2)),        —(X^(RAA))₀₋₁N(R^(AA1))C(═O)R^(AA2), —(X^(RAA))₀₋₁C(═O)OR^(AA1),        —(X^(RAA))₀₋₁OC(═O)R^(AA1), —(X^(RAA))₀₋₁S(O)₁₋₂R^(AA3),        —(X^(RAA))₀₋₁S(O)₁₋₂N(R^(AA1))(R^(AA2)),        —(X^(RAA))₀₋₁N(R^(AA1))S(O)₁₋₂N(R^(AA1))(R^(AA2)),        —(X^(RAA))₀₋₁N(R^(AA1))S(O)₁₋₂(R^(AA3)), and —C(═O)R^(AA1);        wherein X^(RAA) is selected from the group consisting of absent,        C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄        alkynylene; X^(RAA) is optionally substituted with 1 to 3        substituents selected from the group consisting of C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ heteroalkyl and oxo (═O); R^(AA1) and        R^(M2) are each independently selected from the group consisting        of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl and C₁₋₈ haloalkyl;        R^(AA3) is selected from the group consisting of C₁₋₈ alkyl,        C₂₋₈ alkenyl and C₁₋₈ haloalkyl; wherein R^(AA) substituent is        optionally substituted with from 1 to 5 R^(RAA) substituents        selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino and C₁₋₄        dialkylamino;    -   n is an integer from 0 to 5;    -   R^(A) is selected from the group consisting of —(C═O)OR^(A1),        (C₆₋₁₀ aryl)₁₋₂-(X^(RA))—, (5- to 10-membered        heteroaryl)₁₋₂-(X^(RA))—, (C₃₋₁₂ cycloalkyl)₁₋₂-(X^(RA))—, and        (C₂₋₁₁ heterocyclyl)₁₋₂-(X^(RA))—, wherein said C₆₋₁₀ aryl, 5-        to 10 membered heteroaryl, C₃₋₁₂ cycloalkyl and C₂₋₁₁        heterocyclyl of R^(A) is independently optionally substituted        with from 1 to 5 R^(RA) substituents selected from the group        consisting of F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄        alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄        dialkylamino, —N(R^(A1))C(═O)OR^(A3), —OC(═O)N(R^(A1))(R^(A2)),        —N(R^(A1)), —N(R^(A1))C(═O)N(R^(A1))(R^(A2)),        —C(═O)N(R^(A1))(R^(A2)), —N(R^(A1))C(═O)R^(A2), —C(═O)OR^(A1),        —C(═O)OR^(A1), —OC(═O)R^(A1), —S(O)₁₋₂R^(A3),        —S(O)₁₋₂N(R^(A1))(R^(A2)), —N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)),        —N(R^(A1))S(O)₁₋₂(R^(A3)), —C(═O)R^(A1), C₃₋₆ cycloalkyl, C₃₋₆        cycloalkoxy, C₂₋₅ heterocyclyl, C₂₋₅ heterocyclyloxy, 5- to 6        membered heteroaryl and phenyl, wherein the R^(RA) substituent        is optionally substituted with 1 to 5 R^(RAi) substituents        selected from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄(halo)alkoxy, C₁₋₄ alkylamino        and C₁₋₄ dialkylamino; X^(RA) is selected from the group        consisting of absent, —O—, —S—, —N(H)—, —N(C₁₋₄ alkyl)-,        —S(O)₁₋₂—, —S(O)₁₋₂N(H)—, —C(C═O)N(H)—, —C(C═O)N(C₁₋₄ alkyl)-,        —OC(C═O)N(H)—, —N(H)C(C═O)N(H)—, —N(H)S(O)₁₋₂N(H)—, —C(═O)—,        C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄        alkynylene; wherein X^(RA) is optionally substituted with 1 to 3        substituents selected from the group consisting of C₁₋₄ alkyl,        C₁₋₄ haloalkyl, C₁₋₄ heteroalkyl and oxo (═O); R^(A1) and R^(A2)        are each independently selected from the group consisting of        hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈        cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl and C₂₋₇        heterocyclyl; R^(A3) is selected from the group consisting of        C₁₋₈ alkyl, C₂₋₈ alkenyl, C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl,        phenyl, benzyl, 5- to 6-membered heteroaryl and C₂₋₇        heterocyclyl; and    -   q is an integer from 0 to 1;        (ii) C₃₋₁₂ membered carbocycle; wherein    -   R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈        alkoxy, C₁₋₈ alkylamino, C₁₋₈ dialkylamino, C₁₋₈ haloalkyl, F,        Cl, Br, I, —OH, —CN, —NO₂, ═O, —(X^(RA))₀₋₁NR^(A1)R^(A2),        —(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1),        —(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3),        —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)), —(X^(RA))₀₋₁        N(R^(A1))C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2), —(X^(RA))₀₋₁C(═O)OR^(A1),        —(X^(RA))₀₋₁OC(═O)R^(A1), —(X^(RA))₀₋₁S(O)₁₋₂(R^(A3)),        —(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), —C(═O)R^(A1), C₃₋₆        cycloalkyl, C₂₋₅ heterocyclyl, 5- to 10 membered heteroaryl and        phenyl; wherein X^(RA) is selected from the group consisting of        C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄        alkynylene; wherein R^(A1) and R^(A2) are independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, 5- to 6        membered heteroaryl and C₂₋₇ heterocyclyl; R^(A3) is selected        from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈        cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl and C₂₋₇        heterocyclyl; wherein R^(A) substituent is optionally        substituted with from 1 to 5 R^(RA) substituents selected from,        F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino and C₁₋₄ dialkylamino;    -   n is the integer 0; and    -   q is the integer 0 to 6;        (iii) phenyl substituted at the 2-position, the 3,4-positions,        the 2,4-positions, or the 3,5-positions with groups        independently selected from R^(A), wherein each    -   R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈        alkoxy, C₁₋₈ alkylamino, C₁₋₈ dialkylamino, C₁₋₈ haloalkyl, F,        Cl, Br, I, —OH, —CN, —NO₂, ═O, —(X^(RA))₀₋₁NR^(A1)R^(A2),        —(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1),        —(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3),        —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2), —(X^(RA))₀₋₁C(═O)OR^(A1),        —(X^(RA))₀₋₁OC(═O)R^(A1), —(X^(RA))₀₋₁S(O)₁₋₂(R^(A3)),        —(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), —C(═O)R^(A1), C₃₋₆        cycloalkyl, C₃₋₆ cycloalkoxy, C₂₋₅ heterocyclyl, C₂₋₅        heterocycloalkoxy, 5- to 10 membered heteroaryl and phenyl;        wherein X^(RA) is selected from the group consisting of C₁₋₄        alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄        alkynylene; wherein R^(A1) and R^(A2) are independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, 5- to        6-membered heteroaryl and C₂₋₇ heterocyclyl; R^(A3) is selected        from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈        cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl and C₂₋₇        heterocyclyl; wherein R^(A) substituent is optionally        substituted with from 1 to 5 R^(RA) substituents selected from,        F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄ dialkylamino, C₂₋₅        heterocyclyloxy, and C₂₋₇ heterocyclyl that is optionally        substituted with one or more substituents independently selected        from, F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxy, and C₁₋₄ alkoxy carbonyl;        (iv) naphthyl; and (v) 5- to 10-membered heteroaryl comprising        1- to 3-nitrogen atoms and optionally further comprising 1- to        2-heteroatoms selected from O and S; wherein in (iv) and (v)    -   R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈        alkoxy, C₁₋₈ alkylamino, C₁₋₈ dialkylamino, C₁₋₈ haloalkyl, F,        Cl, Br, I, —OH, —CN, —NO₂, ═O, —(X^(RA))₀₋₁NR^(A1)R^(A2),        —(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1),        —(X^(RA))₀₋₁N(R^(A1))C(═O)OR^(A3),        —(X^(RA))₀₋₁OC(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))C(═O)R^(A2), —(X^(RA))₀₋₁C(═O)OR^(A1),        —(X^(RA))₀₋₁OC(═O)R^(A1), —(X^(RA))₀₋₁S(O)₁₋₂(R^(A3)),        —(X^(RA))₀₋₁S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂N(R^(A1))(R^(A2)),        —(X^(RA))₀₋₁N(R^(A1))S(O)₁₋₂(R^(A3)), —C(═O)R^(A1), C₃₋₆        cycloalkyl, C₂₋₅ heterocyclyl, 5- to 10 membered heteroaryl and        phenyl; wherein X^(RA) is selected from the group consisting of        C₁₋₄ alkylene, C₁₋₄ heteroalkylene, C₂₋₄ alkenylene and C₂₋₄        alkynylene; wherein R^(A1) and R^(A2) are independently selected        from the group consisting of hydrogen, C₁₋₈ alkyl, C₂₋₈ alkenyl,        C₁₋₈ haloalkyl, C₃₋₈ cycloalkyl, phenyl, benzyl, 5- to 6        membered heteroaryl and C₂₋₇ heterocyclyl; R^(A3) is selected        from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₃₋₈        cycloalkyl, phenyl, benzyl, 5- to 6-membered heteroaryl and C₂₋₇        heterocyclyl; wherein R^(A) substituent is optionally        substituted with from 1 to 5 R^(RA) substituents selected from,        F, Cl, Br, I, —NH₂, —OH, —CN, —NO₂, ═O, C₁₋₄alkyl,        C₁₋₄haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄ dialkylamino        and C₂₋₅ heterocyclyloxy;    -   n is the integer 0; and    -   q is an integer from 0 to 4.

E3 The compound of E1 or E2, wherein R^(o) is hydrogen.

E4 The compound of E1 or E2, wherein R^(o) is C₁₋₆ alkyl.

E5 The compound of E1 or E2, wherein R^(o) is methyl, ethyl, propyl,isopropyl, butyl, sec-butyl or tert-butyl.

E6 The compound of E1 or E2, wherein R^(o) is ethyl, propyl, isopropyl,butyl, sec-butyl or tert-butyl.

E7 The compound of E1 or E2, wherein R^(o) is methyl.

E8 The compound of any one of E1-E7, wherein R¹ and R² are eachindependently selected from the group consisting of hydrogen, C₁₋₈alkyl, C₁₋₈ haloalkyl and C-s heteroalkyl.

E9 The compound of any one of E1-E7, wherein R¹ and R² are eachindependently selected from the group consisting of hydrogen, methyl,trifluoromethyl, ethyl, propyl, butyl, sec-butyl, tert-butyl,methoxymethyl and methoxyethyl.

E10 The compound of any one of E1-E9, wherein R² is hydrogen.

E11 The compound of any one of E8-E10, wherein R¹ is other than hydrogenand is in the (R)-configuration.

E12 The compound of any one of E8-E10, wherein R¹ is other than hydrogenand is in the (S)-configuration.

E13 The compound of any one of E1-E7, wherein R¹ and R² are combined toform a 3- to 7-membered carbocycle or heterocycle ring comprising 1 to 2heteroatoms selected from N, O and S, and wherein said carbocycle orheterocycle ring are optionally substituted.

E14 The compound of any one of E1-E7, wherein R¹ and R² are combined toform a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl,pyrrolidinyl or piperidinyl ring, and is optionally substituted.

E15 The compound of any one of E1-E7, wherein R¹ and R⁴ are combined toform a 3- to 7-membered heterocycle ring comprising 1 to 2 heteroatomsselected from N, O and S, wherein said heterocycle ring is optionallysubstituted.

E16 The compound of any one of E1-E7, wherein R¹ and R⁴ are combined toform an optionally substituted ring selected from the group consistingof azetidine, pyrrolidine, piperidine, homopiperidine, oxazolidine,thiazolidine, imidazolidine, morpholine, homomorpholine, thiomorpholine,piperazine, and homopiperidine.

E17 The compound of any one of E1-E7, E15, and E16, wherein R^(1/4)substituent is selected from the group consisting of F, Cl, Br, I, —CN,—OH, —NH₂, C₁₋₆ alkyl and C₁₋₈ haloalkyl.

E18 The compound of any one of E1-E7 and E17, wherein a compound ofFormula I has the subformulae I-a:

(I-a)

E19 The compound of any one of E1-E7, wherein in a compound of FormulaI, R² is hydrogen and said compound has the subformula selected from thegroup consisting of:

E20 The compound of any one of E1-E19, wherein R³ is F or Cl; and R⁵ isselected from the group consisting of F, Cl, C₁₋₄ alkyl, C₁₋₄ alkoxy,and C₃₋₈ cycloakyl.

E21 The compound of any one of E1-E19, wherein R³ is F or Cl and R⁵ isselected from the group consisting of F, Cl, cyclopropyl, cyclobutyl andcyclopentyl.

E22 The compound of any one of E1-E21, wherein X¹ is —O— or —N(H)—; X²is absent; the subscript m is 1; and -(L)- is an optionally substitutedC₁₋₄ alkylene.

E23 The compound of any one of E1-E21, wherein X¹ is —O— or —N(H)—; X²is absent; the subscript m is 1; and -(L)- is selected from the groupconsisting of —CH₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—,—C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.

E24 The compound of any one of E1-E23, wherein X¹ is —O—; the subscriptm is 1 and -(L)- is —CH₂—, —C(H)(CH₃)—, or —CH₂—CH₂—.

E25 The compound of any one of E1-E21, wherein X¹ is absent; X² is —O—or —N(H)—; the subscript m is 1; and -(L)- is selected from the groupconsisting of —C(H)₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—,—C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.

E26 The compound of any one of E1-E21, wherein X¹ and X² are absent; thesubscript m is 1; and -(L)- is selected from the group consisting of—C(H)₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—,—C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂— or —CH₂CH₂CH₂CH₂—.

E27 The compound of any one of E1-E21, wherein X¹ and X² are absent; thesubscript m is 1; and -(L)- is selected from the group consisting of—C(H)₂—, —C(═O)—, —C(H)(CH₃)— and —CH₂—CH₂.

E28 The compound of any one of E1-E21, wherein m is 0; X¹ is selectedfrom —O—, and —N(H)—; and X² is absent.

E29 The compound of any one of E1-E28, wherein in Formula I the ring “A”is (i) C₂₋₁₁ heterocycle and is selected from the group consisting ofazetidine, pyrrolidine, piperidine, morpholine, homopiperazine,piperazine and 8-azabicyclo[3.2.1]octane, and is optionally substituted.

E30 The compound of any one of E1-E28, wherein the group

in Formula I is selected from the group consisting of:

E31 The compound of any one of E1-E28, wherein the group

in Formula I is selected from the group consisting of:

E32 The compound of any one of E1-E31, wherein each R^(AA) isindependently selected from the group consisting of methyl,trifluoromethyl, ethyl, F, Cl, Br. and 1.

E33 The compound of any one of E1-E32, wherein each R^(A) isindependently selected from the group consisting of(phenyl)₁₋₂-(X^(RA))—, (5-6 membered heteroaryl)₁₋₂-(X^(RA)), whereinsaid phenyl or said 5-6 membered heteroaryl is optionally substitutedwith from 1 to 5 substituents selected from, F, Cl, Br, —NH₂, —OH, —CN,—NO₂, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄dialkylamino, phenyl, C₁₋₄ alkanoyl, C₁₋₄ alkyl-OC(═O)— and C₃₋₆cycloalkyl; and wherein X^(RA) is selected from the group consisting ofabsent, —O—, —S—, —N(H)—, —N(C₁₋₄ alkyl)-, C₁₋₄ alkylene,C₁₋₄-heteroalkylene, C₂₋₄ alkenylene and C₂₋₄ alkynylene; and whereinX^(RA) is optionally substituted with 1 to 3 substituents selected fromthe group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, and C₁₋₄heteroalkyl.

E34 The compound of E33, wherein R^(A) is (phenyl)-(X^(RA))— or (5-6membered heteroaryl)-(X^(RA))—.

E35 The compound of E34, wherein each R^(A) is independently selectedfrom the group consisting

E36 The compound of any one of E1-E28, wherein the group

in Formula I is selected from the group consisting of:

E37 The compound of any one of E1-E28, wherein in Formula I the ring “A”is (ii) C₃₋₁₂ carbocycle selected from the group consisting ofcyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane,adamantane, cubane, bicyclo[2.1.1]hexane, bicyclo[2.2.2]octane,bicyclo[4.1.1]octane, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[3.2.1]octane, bicyclo[3.3.1]nonane, bicyclo[3.1.0]hexane,tetrahydronaphthyl, spiro[2,5]octane, norpinane, spiro[3.5]nonanyl,norbornanyl, spiro[4.5]decane, bicyclo[4.1.0]heptane andspiro[5.5]undecanyl, and is optionally substituted.

E38 The compound of E37, wherein each R^(A) is independently selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ alkoxy, C₁₋₈ alkylamino,C₁₋₈ dialkylamino, C₁₋₈ haloalkyl, F, Cl, Br, I, —OH, —CN, —NO₂, ═O,—(X^(RA))₀₋₁NR^(A1)R^(A2), —(X^(RA))₀₋₁OR^(A1), —(X^(RA))₀₋₁SR^(A1),—(X^(RA))₀₋₁C(═O)N(R^(A1))(R^(A2)) and —(X^(RA))⁰⁻¹C(═O)OR^(A1).

E39 The compound of E38, wherein each R^(A) is independently selectedfrom the group consisting of, fluoro, methyl, cyano, andtrifluoromethyl.

E40 The compound of any one of E1-E28, wherein the group

in Formula I is selected from the group consisting of:

E41 The compound of any one of E1-E28, wherein the group

in Formula I is selected from the group consisting of:

E42 The compound of any one of E1-E28, wherein the group

Formula I is selected from the group consisting of:

E43 The compound of E42 wherein each R^(A) is independently selectedfrom the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl, F, Cl, Br, I,—OH, —CN, —(X^(RA))₀₋₁NR^(A1)R^(A2), —(X^(RA))₀₋₁OR^(A1),—(X^(RA))₀₋₁SR^(A1), —C(═O)R^(A1), C₃₋₆ cycloalkyl, C₂₋₅ heterocyclyl,5- to 10 membered heteroaryl and phenyl, wherein R^(A) is furtheroptionally substituted.

E44 The compound of any one of E1-E28, wherein the group

in Formula I is selected from the group consisting of:

E45 The compound of any one of E1-E28, wherein in Formula I the ring “A”is (iv) naphthyl; or (v) 5- to 10-membered heteroaryl selected from thegroup consisting of pyridine, pyrimidine, pyridazine and pyrazine, andwherein (iv) and (v) are optionally substituted with from 1 to 3 R^(A)group selected from the group consisting of C₁₋₈ alkyl, C₁₋₈ haloalkyl,F, Cl, Br, I, —OH, —CN, —(X^(RA))₀₋₁NR^(A1)R^(A2), —(X^(RA))₀₋₁OR_(A1),—(X^(RA))₀₋₁SR^(A1), —C(═O)R^(A1), C₃₋₆ cycloalkyl, C₂₋₅ heterocyclyl,5- to 10 membered heteroaryl and phenyl, and wherein R^(A) is furtheroptionally substituted.

E46 The compound of any one of E1-E28, wherein the group

in Formula I is selected from the group consisting of:

E47 The compound of any one of E1-E28, wherein the group

in Formula I is selected from the group consisting of:

E48 The compound of E1, wherein the group

in Formula I is selected from the group consisting of:

E49 A compound as described in E1 or E2, or a pharmaceuticallyacceptable salt to thereof, wherein:

R^(o) is hydrogen or C₁₋₆ alkyl;

R¹ and R² are each independently selected from the group consisting ofhydrogen and C₁₋₈ alkyl;

or R¹ and R² are combined to form a 3- to 7-membered;

or R¹ and R⁴ are combined to form a 3- to 7-membered heterocycle ringcomprising 1 to 2 heteroatoms selected from N, O and S wherein saidheterocycle ring is optionally substituted with 1 to 3 R^(1/4)substituents selected from the group consisting of F and —OH; and R² ishydrogen;R³ is selected from the group consisting of hydrogen and F;R⁴ is selected from the group consisting of hydrogen or C₁₋₄ alkyl; orR¹ and R⁴ are combined to form a 3- to 7-membered heterocycle ring asdescribed above;R⁵ is selected from the group consisting of F, Cl, C₁₋₈ alkyl, and C₃₋₈cycloalkyl;L is C₁₋₆ alkylene;the subscript m represents the integer 0 or 1;X¹ and X² are each independently selected from the group consisting ofabsent and —O—, andwherein if the subscript m is 0 then one of X¹ or X² is absent;the ring “A” in is selected from the group consisting of:(i) C₂₋₁₁ heterocycle comprising a nitrogen atom and further optionallycomprising 1-2 heteroatoms selected from N, O and S; wherein

-   -   R^(AA) is independently selected from the group consisting of        C₁₋₈ alkyl, C₁₋₈ haloalkyl, C₁₋₈ heteroalkyl, F, Cl, Br and I;    -   n is an integer from 0 to 5;    -   R^(A) is selected from the group consisting of (C₆₋₁₀        aryl)₁₋₂-(X^(RA))— and (5- to 10-membered        heteroaryl)₁₋₂-(X^(RA))—, wherein said C₆₋₁₀ aryl, 5- to 10        membered heteroaryl R^(A) is independently optionally        substituted with from 1 to 5 R^(RA) substituents selected from        the group consisting of F, Cl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy and        phenyl, wherein the R^(RA) substituent is optionally substituted        with 1 to 5 R^(RAi) substituents selected from F and Cl; X^(RA)        is selected from the group consisting of absent, —O—, —S—,        —N(H)—, —N(C₁₋₄ alkyl)-, —S(O)₂—, —C(═O)—, C₁₋₄ alkylene; and    -   q is an integer from 0 to 1;        (ii) C₃₋₁₂ membered carbocycle; wherein    -   R^(A) is selected from the group consisting of C₁₋₈ alkyl, C₁₋₈        haloalkyl, F, and —CN;    -   n is the integer 0; and    -   q is the integer 0 to 6:        (iii) phenyl substituted at the 2-position, the 3,4-positions,        the 2,4-positions, or the 3,5-positions with groups        independently selected from R^(A), wherein each    -   R^(A) is selected from the group consisting of Cl, —OR^(A1), 5-        to 10 membered heteroaryl and phenyl; R^(A1) is C₁₋₈ haloalkyl;        wherein each R^(A) substituent is optionally substituted with        from 1 to 5 R^(RA) substituents selected from, —NH₂, and C₂₋₇        heterocyclyl that is optionally substituted with one or more        C₁₋₄ alkoxycarbonyl;        and (v) 5- to 10-membered heteroaryl comprising 1- to 3-nitrogen        atoms and optionally further comprising 1- to 2-heteroatoms        selected from O and S; wherein (v)    -   R^(A) is selected from the group consisting of Cl, —OR^(A1), and        C₃₋₆ cycloalkyl; wherein R^(A1) is C₁₋₈ haloalkyl;    -   n is the integer 0; and    -   q is an integer from 0 to 4.

E50. A compound as described in any one of E1, E3-E17, and E20-E49wherein D is absent.

E51. A compound as described in any one of E1, E3-E17, and E20-E49wherein D is —CH₂—.

E52. A compound as described in any one of claims E1, E3-E17, andE20-E51 wherein E is tetrazolyl.

E53. A compound as described in any one of E1, E3-E17, and E20-E51wherein E is —C(═O)OR^(o).

E54. A compound as described in any one of E1, E3-E17, and E20-E51wherein E is —C(═O)NR^(oa)R^(ob).

E55. A compound as described in E54 wherein R^(oa) is hydrogen andR^(ob) is hydrogen or hydroxyl.

E56. A compound as described in any one of wherein D is absent and E is—C(═O)OR^(o).

E57 A compound selected from the group consisting of

and salts thereof.

E58 A compound selected from the group consisting of:

and salts thereof.

E59 The compound of any one of E1-E58 which is not:

or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt thereof as described in any one of E1-E51, and apharmaceutically acceptable excipient.

In another aspect the present invention provides for a method oftreating a disease or condition in a mammal selected from the groupconsisting of pain, depression, cardiovascular diseases, respiratorydiseases, and psychiatric diseases, and combinations thereof, whereinthe method comprises administering to the mammal in need thereof atherapeutically effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof as described in any one ofE1-E51. In another aspect of the present invention said disease orcondition is selected from the group consisting of neuropathic pain,inflammatory pain, visceral pain, cancer pain, chemotherapy pain, traumapain, surgical pain, post-surgical pain, childbirth pain, labor pain,neurogenic bladder, ulcerative colitis, chronic pain, persistent pain,peripherally mediated pain, centrally mediated pain, chronic headache,migraine headache, sinus headache, tension headache, phantom limb pain,dental pain, peripheral nerve injury or a combination thereof. Inanother aspect of the present invention said disease or condition isselected from the group consisting of pain associated with HIV, HIVtreatment induced neuropathy, trigeminal neuralgia, post-herpeticneuralgia, eudynia, heat sensitivity, tosarcoidosis, irritable bowelsyndrome, Crohns disease, pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheralneuropathy, arthritis, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomvolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxi related illnesses, familialervthromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscause by stroke or neural trauma, tach-arrhythmias, atrial fibrillationand ventricular fibrillation.

In another aspect the present invention provides for a method oftreating pain in a mammal by the inhibition of ion flux through avoltage-dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof as described in any one of E1-E59.

In another aspect the present invention provides for a method ofdecreasing ion flux through a voltage-dependent sodium channel in a cellin a mammal, wherein the method comprises contacting the cell with acompound of formula I, or a pharmaceutically acceptable salt thereof asdescribed in any one of E1-E59.

In another aspect the present invention provides for a method oftreating pruritus in a mammal, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of a compound of formula I, or a pharmaceutically acceptable saltthereof as described in any one of E1-E59.

In another aspect the present invention provides for a method oftreating cancer in a mammal, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount acompound of formula I, or a pharmaceutically acceptable salt thereof asdescribed in any one of E1-E59.

In another aspect the present invention provides for a method oftreating, but not preventing, pain in a mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of a compound of formula I, or a pharmaceuticallyacceptable salt thereof as described in any one of E1-E59. In anotheraspect of the present invention the pain is selected from the groupconsisting of neuropathic pain, inflammatory pain, visceral pain, cancerpain, chemotherapy pain, trauma pain, surgical pain, post-surgical pain,childbirth pain, labor pain, neurogenic bladder, ulcerative colitis,chronic pain, persistent pain, peripherally mediated pain, centrallymediated pain, chronic headache, migraine headache, sinus headache,tension headache, phantom limb pain, dental pain, peripheral nerveinjury or a combination thereof. In another aspect the present inventionthe pain is associated with a disease or condition selected from thegroup consisting of HIV, HIV treatment induced neuropathy, trigeminalneuralgia, post-herpetic neuralgia, eudynia, heat sensitivity,tosarcoidosis, irritable bowel syndrome, Crohns disease, pain associatedwith multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS),diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoidarthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia,myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxi related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscause by stroke or neural trauma, tach-arrhythmias, atrial fibrillationand ventricular fibrillation.

In another aspect the present invention provides for a method for thetreatment or prophylaxis of pain, depression, cardiovascular disease,respiratory disease, or psychiatric disease, or a combinations thereof,in an animal which method comprises administering an effective amount ofa compound of formula I, or a pharmaceutically acceptable salt thereofas described in any one of E1-E59.

In another aspect the present invention provides for a compound offormula I, or a pharmaceutically acceptable salt thereof as described inany one of E1-E59 for the use as a medicament for the treatment ofdiseases and disorders selected from the group consisting of pain,depression, cardiovascular diseases, respiratory diseases, andpsychiatric diseases, or a combination thereof.

In another aspect the present invention provides for the use of acompound of formula I, or a pharmaceutically acceptable salt thereof asdescribed in any one of E1-E59 for the manufacture of a medicament forthe treatment of diseases and disorders selected from the groupconsisting of pain, depression, cardiovascular diseases, respiratorydiseases, and psychiatric diseases, or a combination thereof.

In another aspect the present invention provides a compound as describedin the Examples hereinbelow, or a free-base or a salt thereof.

In another aspect the present invention provides for the invention asdescribed herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “alkyl”, by itself or as part of anothersubstituent, means, unless otherwise stated, a straight or branchedchain hydrocarbon radical, having the number of carbon atoms designated(i.e., C₁₋₈ means one to eight carbons). Examples of alkyl groupsinclude methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl,iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike. The term “alkenyl” refers to an unsaturated alkyl radical havingone or more double bonds. Similarly, the term “alkynyl” refers to anunsaturated alkyl radical having one or more triple bonds. Examples ofsuch unsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chainhydrocarbon radical, consisting of the stated number of carbon atoms andfrom one to three heteroatoms selected from the group consisting of O,N, Si and S, and wherein the nitrogen and sulfur atoms can optionally beoxidized and the nitrogen heteroatom can optionally be quaternized. Theheteroatom(s) O, N and S can be placed at any interior position of theheteroalkyl group. The heteroatom Si can be placed at any position ofthe heteroalkyl group, including the position at which the alkyl groupis attached to the remainder of the molecule. A “heteroalkyl” cancontain up to three units of unsaturation, and also include mono- andpoly-halogenated variants, or combinations thereof. Examples include—CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—CF₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃—CH₂—CH═N—OCH₃, and —CH═CH═N(CH₃)—CH₃. Up to two heteroatomscan be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane (including branched alkane), asexemplified by —CH₂CH₂CH₂CH₂— and —CH(CH₂)CH₂CH₂—. Typically, an alkyl(or alkylene) group will have from 1 to 24 carbon atoms, with thosegroups having 10 or fewer carbon atoms being preferred in the presentinvention. “Alkenylene” and “alkynylene” refer to the unsaturated formsof “alkylene” having double or triple bonds, respectively. “Alkylene”,“alkenylene” and “alkynylene” are also meant to include mono andpoly-halogenated variants.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— and—S—CH₂—C≡C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like). The term “heteroalkylene”is also meant to include mono and poly-halogenated variants.

The terms “alkoxy,” “alkylamino” and “alkylthio”, are used in theirconventional sense, and refer to those alkyl groups attached to theremainder of the molecule via an oxygen atom (“oxy”), an amino group(“amino”) or thio group, and further include mono- and poly-halogenatedvariants thereof. Additionally, for dialkylamino groups, the alkylportions can be the same or different.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. The term “(halo)alkyl” is meant to include botha “alkyl” and “haloalkyl” substituent. Additionally, the term“haloalkyl,” is meant to include monohaloalkyl and polyhaloalkyl. Forexample, the term “C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, andthe like.

The term “aryl” as used herein refers to a single all carbon aromaticring or a multiple condensed all carbon ring system wherein at least oneof the rings is aromatic. For example, in certain embodiments, an arylgroup has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbonatoms. Aryl includes a phenyl radical. Aryl also includes multiplecondensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings)having about 9 to 20 carbon atoms in which at least one ring is aromaticand wherein the other rings may be aromatic or not aromatic (i.e.,carbocycle). Such multiple condensed ring systems are optionallysubstituted with one or more (e.g., 1, 2 or 3) oxo groups on anycarbocycle portion of the multiple condensed ring system. The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Itis to be understood that the point of attachment of a multiple condensedring system, as defined above, can be at any position of the ring systemincluding an aromatic or a carbocycle portion of the ring. Non-limitingexamples of aryl groups include, but are not limited to, phenyl,indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and thelike.

The term “carbocycle” or “carbocyclyl” refers to a single saturated(i.e., cycloalkyl) or a single partially unsaturated (e.g.,cycloalkenyl, cycloalkadienyl, etc.) all carbon ring having 3 to 7carbon atoms (i.e., (C₃-C₇)carbocycle). The term “carbocycle” or“carbocyclyl” also includes multiple condensed, saturated and partiallyunsaturated all carbon ring systems (e.g., ring systems comprising 2, 3or 4 carbocyclic rings). Accordingly, carbocycle includes multicycliccarbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycleshaving about 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane andbicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic andtetracyclic carbocycles with up to about 20 carbon atoms). The rings ofthe multiple condensed ring system can be connected to each other viafused, spiro and bridged bonds when allowed by valency requirements. Forexample, multicyclic carbocyles can be connected to each other via asingle carbon atom to form a spiro connection (e.g., spiropentane,spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fusedconnection (e.g., carbocycles such as decahydronaphthalene, norsabinane,norcarane) or via two non-adjacent carbon atoms to form a bridgedconnection (e.g., norbornane, bicyclo[2.2.2]octane, etc). The“carbocycle” or “carbocyclyl” can also be optionally substituted withone or more (e.g., 1, 2 or 3) oxo groups. In one embodiment the termcarbocycle includes a C₃₋₁₂ carbocycle. In one embodiment the termcarbocycle includes a C₃₋₈ carbocycle. In one embodiment the termcarbocycle includes a C₃₋₆ carbocycle. In one embodiment the termcarbocycle includes a C₃₋₅ carbocycle. Non-limiting examples ofcarbocycles include cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, bicyclo[2.2.1]heptane, pinane,adamantane, norborene, spirocyclic C₅₋₁₂ alkane, and 1-cyclohex-3-enyl.

The term “heteroaryl” as used herein refers to a single aromatic ringthat has at least one atom other than carbon in the ring, wherein theatom is selected from the group consisting of oxygen, nitrogen andsulfur; “heteroaryl” also includes multiple condensed ring systems thathave at least one such aromatic ring, which multiple condensed ringsystems are further described below. Thus, “heteroaryl” includes singlearomatic rings of from about 1 to 6 carbon atoms and about 1-4heteroatoms selected from the group consisting of oxygen, nitrogen andsulfur. The sulfur and nitrogen atoms may also be present in an oxidizedform provided the ring is aromatic. Exemplary heteroaryl ring systemsinclude but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.“Heteroaryl” also includes multiple condensed ring systems (e.g., ringsystems comprising 2, 3 or 4 rings) wherein a heteroaryl group, asdefined above, is condensed with one or more rings selected fromheteroaryls (to form for example a naphthyridinyl such as1,8-naphthyridinyl), heterocycles, (to form for example a 1, 2, 3,4-tetrahydronaphthyridinyl such as1,2,3,4-tetrahydro-1,8-naphthyridinyl), carbocycles (to form for example5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) toform the multiple condensed ring system. Thus, a heteroaryl (a singlearomatic ring or multiple condensed ring system) has about 1-20 carbonatoms and about 1-6 heteroatoms within the heteroaryl ring. Suchmultiple condensed ring systems may be optionally substituted with oneor more (e.g., 1, 2, 3 or 4) oxo groups on the carbocycle or heterocycleportions of the condensed ring. The rings of the multiple condensed ringsystem can be connected to each other via fused, spiro and bridged bondswhen allowed by valency requirements. It is to be understood that theindividual rings of the multiple condensed ring system may be connectedin any order relative to one another. It is also to be understood thatthe point of attachment of a multiple condensed ring system (as definedabove for a heteroaryl) can be at any position of the multiple condensedring system including a heteroaryl, heterocycle, aryl or carbocycleportion of the multiple condensed ring system. It is also to beunderstood that the point of attachment for a heteroaryl or heteroarylmultiple condensed ring system can be at any suitable atom of theheteroaryl or heteroaryl multiple condensed ring system including acarbon atom and a heteroatom (e.g., a nitrogen). Exemplary heteroarylsinclude but are not limited to pyridyl, pyrrolyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl,quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl,quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl,benzimidazolyl, thianaphthenyl, pyrrolo[2,3-b]pyridinyl,quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7-tetrahydro-1H-indazole and3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclo-penta[1,2-c]pyrazole.

The term “heterocyclyl,” “heterocycloalkyl,” or “heterocycle” as usedherein refers to a single saturated or partially unsaturated ring thathas at least one atom other than carbon in the ring, wherein the atom isselected from the group consisting of oxygen, nitrogen and sulfur; theterm also includes multiple condensed ring systems that have at leastone such saturated or partially unsaturated ring, which multiplecondensed ring systems are further described below. Thus, the termincludes single saturated or partially unsaturated rings (e.g., 3, 4, 5,6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1to 3 heteroatoms selected from the group consisting of oxygen, nitrogenand sulfur in the ring. The ring may be substituted with one or more(e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may alsobe present in their oxidized forms. Exemplary heterocycles include butare not limited to azetidinyl, tetrahydrofuranyl and piperidinyl. Theterm “heterocycle” also includes multiple condensed ring systems (e.g.,ring systems comprising 2, 3 or 4 rings) wherein a single heterocyclering (as defined above) can be condensed with one or more groupsselected from heterocycles (to form for example a1,8-decahydronapthyridinyl), carbocycles (to form for example adecahydroquinolyl) and aryls to form the multiple condensed ring system.Thus, a heterocycle (a single saturated or single partially unsaturatedring or multiple condensed ring system) has about 2-20 carbon atoms and1-6 heteroatoms within the heterocycle ring. Such multiple condensedring systems may be optionally substituted with one or more (e.g., 1, 2,3 or 4) oxo groups on the carbocycle or heterocycle portions of themultiple condensed ring. The rings of the multiple condensed ring systemcan be connected to each other via fused, spiro and bridged bonds whenallowed by valency requirements. It is to be understood that theindividual rings of the multiple condensed ring system may be connectedin any order relative to one another. It is also to be understood thatthe point of attachment of a multiple condensed ring system (as definedabove for a heterocycle) can be at any position of the multiplecondensed ring system including a heterocycle, aryl and carbocycleportion of the ring. It is also to be understood that the point ofattachment for a heterocycle or heterocycle multiple condensed ringsystem can be at any suitable atom of the heterocycle or heterocyclemultiple condensed ring system including a carbon atom and a heteroatom(e.g., a nitrogen). In one embodiment the term heterocycle includes aC₂₋₂₀ heterocycle. In one embodiment the term heterocycle includes aC₂₋₇ heterocycle. In one embodiment the term heterocycle includes a C₂₋₅heterocycle. In one embodiment the term heterocycle includes a C₂₋₄heterocycle. Exemplary heterocycles include, but are not limited toaziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl,dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl,1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl,1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,1,4-benzodioxanyl, spiro[cyclopropane-1,1′-isoindolinyl]-3′-one,isoindolinyl-1-one, 2-oxa-6-azaspiro[3.3]heptanyl, imidazolidin-2-oneN-methylpiperidine, imidazolidine, pyrazolidine, butyrolactam,valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide,1,4-dioxane, thiomorpholine, thiomorpholine-S-oxide,thiomorpholine-S,S-oxide, pyran, 3-pyrroline, thiopyran, pyrone,tetrahydrothiophene, quinuclidine, tropane, 2-azaspiro[3.3]heptane,(1R,5S)-3-azabicyclo[3.2.1 l]octane, (1s,4s)-2-azabicyclo[2.2.2]octane,(1R,4R)-2-oxa-5-azabicyclo[2.2.2]octane and pyrrolidin-2-one.

The term “heterocyclyloxy” as used herein refers to a group(heterocyclyl)-O—, wherein the term heterocyclyl has the meaning definedherein.

The term “alkoxycarbonyl” as used herein refers to a group(alkyl)-O—C(═O)—, wherein the term alkyl has the meaning defined herein.

The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in someembodiments, will include both substituted and unsubstituted forms ofthe indicated radical. Preferred substituents for each type of radicalare provided below Substituents for the alkyl radicals (including thosegroups often referred to as alkylene, alkenyl, alkynyl, heteroalkyl,carbocycle, and heterocyclyl) can be a variety of groups including, butnot limited to, -halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′,—C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′″C(O)NR′R″,—NR″C(O)₂R′, —NHC(NH₂)═N H, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′,—NR′″C(NR′R″)═N—CN, —NR′″C(NR′R″)═NOR′, —NHC(NH₂)═NR′, —S(O)R′,—S(O)₂R′, —S(O)₂NR′R″, —NR'S(O)₂R″, —NR′″S(O)₂NR′R″, —CN, —NO₂,—(CH₂)₁₋₄—OR′, —(CH₂)₁₋₄—NR′R″, —(CH₂)₁₋₄—SR′, —(CH₂)₁₋₄—SiR′R″R′″,—(CH₂)₁₋₄—OC(O)R′, —(CH₂)₁₋₄—C(O)R′, —(CH₂)₁₋₄—CO₂R′, —(CH₂)₁₋₄CONR′R″,in a number ranging from zero to (2m′+1), where m′ is the total numberof carbon atoms in such radical. R′, R″ and R′″ each independently refergroups including, for example, hydrogen, unsubstituted C₁₋₆ alkyl,unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3halogens, unsubstituted C₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆ alkylthiogroups, or unsubstituted aryl-C₁₋₄ alkyl groups, unsubstitutedheteroaryl, substituted to heteroaryl, among others. When R′ and R″ areattached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ is meant to include 1-pyrrolidinyl and 4-morpholinyl. Othersubstituents for alkyl radicals, including heteroalkyl, alkylene,include for example, ═O, ═NR′, ═N—OR′, ═N—CN, ═NH, wherein R′ includesubstituents as described above.

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from the group including, but not limited tohalogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′, —CONR′R″,—C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′, —NR′C(O)NR″R′″,—NHC(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR′S(O)₂R″, —N, perfluoro-C₁₋₄ alkoxy, andperfluoro-C₁₋₄alkyl, —(CH₂)₁₋₄—OR′, —(CH₂)₁₋₄—NR′R″, —(CH₂)₁₋₄—SR′,—(CH₂)₁₋₄—SiR′R″R′″, —(CH₂)₁₋₄—OC(O)R′, —(CH₂)₁₋₄—C(O)R′,—(CH₂)₁₋₄—CO₂R′, —(CH₂)₁₋₄CONR′R″, in a number ranging from zero to thetotal number of open valences on the aromatic ring system; and where R′,R″ and R′″ are independently selected from hydrogen, C₁₋₆ alkyl, C₃₋₆carbocycle, C₂₋₆ alkenyl, C₂₋₆ alkynyl, unsubstituted aryl andheteroaryl, (unsubstituted aryl)-C₁₋₄ alkyl, and unsubstitutedaryloxy-C₁₋₄ alkyl. Other suitable substituents include each of theabove aryl substituents attached to a ring atom by an alkylene tether offrom 1-4 carbon atoms. When a substituent for the aryl or heteroarylgroup contains an alkylene linker (e.g., —(CH₂)₁₋₄—NR′R″), the alkylenelinker includes halo variants as well. For example, the linker“—(CH₂)₁₋₄—” when used as part of a substituent is meant to includedifluoromethylene, 1,2-difluoroethylene, etc.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

As used herein, the term “chiral” refers to molecules which have theproperty of non-superimposability of the mirror image partner, while theterm “achiral” refers to molecules which are superimposable on theirmirror image partner.

As used herein, the term “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicates the point ofattachment of the bond that the wavy bond intersects in the chemicalstructure to the remainder of a molecule.

As used herein, the term “C-linked” means that the group that the termdescribes is attached the remainder of the molecule through a ringcarbon atom.

As used herein, the term “N-linked” means that the group that the termdescribes is attached to the remainder of the molecule through a ringnitrogen atom.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers can separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”. John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention can contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer can also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which canoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

As used herein, the term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

As used herein, the term “solvate” refers to an association or complexof one or more solvent molecules and a compound of the invention.Examples of solvents that form solvates include, but are not limited to,water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,and ethanolamine. The term “hydrate” refers to the complex where thesolvent molecule is water.

As used herein, the term “protecting group” refers to a substituent thatis commonly employed to block or protect a particular functional groupon a compound. For example, an “amino-protecting group” is a substituentattached to an amino group that blocks or protects the aminofunctionality in the compound. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitable protectinggroups include acetyl and silyl. A “carboxy-protecting group” refers toa substituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see P. G. M. Wuts and T. W. Greene. Greene's Protective Groups inOrganic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein, the term “mammal” includes, but is not limited to,humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,pigs, and sheep.

As used herein, the term “pharmaceutically acceptable salts” is meant toinclude salts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example.Berge, S. M., et al., “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. As used herein the term “prodrug” refers tothose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues, is covalently joined through an amide orester bond to a free amino, hydroxy or carboxylic acid group of acompound of the present invention. The amino acid residues include butare not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,omithine, 3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyricacid, citrulline, homocysteine, homoserine, methyl-alanine,para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine,methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁₋₆)alkanoyloxymethyl,1-((C₁₋₆)alkanoyloxy)ethyl, I-methyl-1-((C₁₋₆)alkanoyloxy)ethyl,(C₁₋₄)alkoxycarbonyloxymethyl, N—(C₁₋₆) alkoxycarbonylaminomethyl,succinoyl, (C₁₋₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(OXO(C₁₋₆)alkyl)₂ or glycosyl (theradical resulting from the removal of a hydroxyl group of the hemiacetalform of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985): b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992), d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites ofcompounds of the invention. As used herein, a “metabolite” refers to aproduct produced through metabolism in the body of a specified compoundor salt thereof. Such products can result for example from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention can exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention.

The compounds of the present invention can also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the present invention alsoembraces isotopically-labeled variants of the present invention whichare identical to those recited herein, bur the for the fact that one ormore atoms are replace by an atom having the atomic mass or mass numberdifferent from the predominant atomic mass or mass number usually foundin nature for the atom. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedin to compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine,such as ²H (“D”), ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P,³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically labeled compounds ofthe present invention (e.g., those labeled with ³H or ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (³H) andcarbon-14 (¹⁴C) isotopes are useful for their ease of preparation anddetectability. Further substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Positron emitting isotopes such as ¹⁵O, ³N, ¹¹C, and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of thepresent inventions can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

The terms “treat” and “treatment” refer to both therapeutic treatmentand/or prophylactic treatment or preventative measures, wherein theobject is to prevent or slow down (lessen) an undesired physiologicalchange or disorder, such as, for example, the development or spread ofcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease or disorder, stabilized (i.e., notworsening) state of disease or disorder, delay or slowing of diseaseprogression, amelioration or palliation of the disease state ordisorder, and remission (whether partial or total), whether detectableor undetectable. “Treatment” can also mean prolonging survival ascompared to expected survival if not receiving treatment. Those in needof treatment include those already with the disease or disorder as wellas those prone to have the disease or disorder or those in which thedisease or disorder is to be prevented.

The phrase “therapeutically effective amount” or “effective amount”means an amount of a compound of the present invention that (i) treatsor prevents the particular disease, condition, or disorder, (ii)attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, condition,or disorder described herein. For cancer therapy, efficacy can, forexample, be measured by assessing the time to disease progression (TTP)and/or determining the response rate (RR).

The term “bioavailability” refers to the systemic availability (i.e.,blood/plasma levels) of a given amount of drug administered to apatient. Bioavailability is an absolute term that indicates measurementof both the time (rate) and total amount (extent) of drug that reachesthe general circulation from an administered dosage form.

A. Compounds

In one aspect the present invention provides for compounds of Formula Iand its embodiments as described hereinbove.

In another embodiment, the compound is selected from compounds offormula I as described in the Examples herein and salts thereof.

Synthesis of Compounds

Compounds of formula (I) may be prepared by the process illustrated inSchemes 1 and 2. Compounds of formula (I), wherein X¹ is O, S, or NH,may be prepared by the process illustrated in Scheme 1.

Compounds of formula (I) can be made according to step (ix) fromcompounds of formula (IX) by treatment with an acid (when R is t-butyl)such as trifluoroacetic acid, hydrogen chloride or by basic hydrolysisunder a condition in the presence of a base such as lithium hydroxide,sodium hydroxide.

Compounds of formula (IX) can be made from compounds of formula (II) bydisplacement with formula (III) and a base (reaction step ii in Scheme1). Suitable conditions include potassium tert-butoxide in DMSO, NaH inDMF or K₂CO₃ in DMF. Formula (II) can be made according to step (i)amide formation conditions by activation of the acid group of formula(IV) with reagents such as oxalyl chloride, carbonyl di-imidazole (CDl),propylphosphonic anhydride, a uronium based amide coupling reagent or acarbodiimide reagent followed by displacement with a formula (VII).

Alternatively, compounds of formula (IX) can be made from compounds offormula (IV) by reversing steps (i) and (ii) as described in Scheme 1.Illustrative conditions for steps vi and vii are as previously describedin steps (ii) and (i), respectively.

Compounds of formula (IX) can also be made from compounds of formula (V)according to step (v) by displacement of the ester (when OPg is asuitable ester leaving group) with compounds of formula (VII) and asuitable base such as potassium tert-butoxide, NaH or DBU.

Compounds of formula (IX) can also be made from compounds of formula (V)by a two steps sequence (see steps viii and vii in Scheme 1). Compoundsof formula (V) can be made from compounds of formula (VIII) according tostep (iv) via a nucleophilic substitution reaction using compounds offormula (III) and a base as described in step ii. Compounds of formula(VIII) can be made from compounds of formula (IV) according to step(iii) using protecting group methodology as described in references suchas ‘Greene's Protective Groups in Organic Synthesis’. When Pg is tolyl,illustrative conditions comprise thionyl chloride or carbonyldiimidazolewith para-cresol. When Pg is tert-butyl, illustrative conditionscomprise di-tert butyl dicarbonate and 4-dimethylaminopyridine intert-butanol.

Compounds of formula (I), wherein R⁵ is Ar, heteroaryl, C₁₋₈ alkyl, C₁₋₈haloalkyl, C₁₋₈ alkoxy, C₃₋₁₀ cycloalkyl or C₂₋₉ heterocycloalkyl can beprepared from compounds of formula (V) in Scheme 2 by a sequenceillustrative in scheme 1 (step v or steps viii and vii).

Compounds of formula (V) can be prepared by palladium-catalyzed couplingof a compound of formula (R₅M) according to step (ii) from compounds offormula (XI) as described in Scheme 2, which can be prepared undersimilar conditions as illustrated in Scheme 1 (step iii and step iv),wherein X is a halide, such as Cl, Br or I. Conveniently the coupling iseffective with a boronic acid or ester of formula (R₅M). The couplingreaction can be carried out with a variety of palladium catalysts suchas palladium acetate or tetrakistriphenylphosphine palladium (0) invarious solvents and in the presence of bases such as sodium andpotassium carbonate, cesium fluoride or potassium phosphate.

Compounds of formula (I), wherein the moiety —X²-(L)m-X¹— is OCHR⁶,SCHR⁶, or NR⁷CHR⁶ may be prepared from compounds of formula (V), eitherR⁶ and/or R⁷ is H. or alkyl substitutions. Compounds of formula (V) canbe prepared from compounds of formula (XII) under either basic or acidicconditions by the process illustrated in Scheme 3, Y is a halide,mesylate, tosylate or 2,2,2-trichloroacetimidate.

B. Pharmaceutical Compositions and Administration

In addition to one or more of the compounds provided above (orstereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, pharmaceutically acceptable salts, or prodrugs thereof), theinvention also provides for compositions and medicaments comprising acompound of formula I or and embodiment thereof and at least onepharmaceutically acceptable carrier, diluent or excipient. Thecompositions of the invention can be used to selectively inhibit NaV1.7in patients (e.g, humans).

The term “composition,” as used herein, is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In one embodiment, the invention provides for pharmaceuticalcompositions (or medicaments) comprising a compound of formula I or anembodiment thereof, and its stereoisomers, geometric isomers, tautomers,solvates, metabolites, isotopes, pharmaceutically acceptable salts, orprodrugs thereof) and a pharmaceutically acceptable carrier, diluent orexcipient. In another embodiment, the invention provides for preparingcompositions (or medicaments) comprising compounds of the invention. Inanother embodiment, the invention provides for administering compoundsof formula I or its embodiments and compositions comprising compounds offormula I or an embodiment thereof to a patient (e.g., a human patient)in need thereof.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The effective amount of the compound tobe administered will be governed by such considerations, and is theminimum amount necessary to inhibit NaV1.7 activity as required toprevent or treat the undesired disease or disorder, such as for example,pain. For example, such amount may be below the amount that is toxic tonormal cells, or the mammal as a whole.

In one example, the therapeutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg ofpatient body weight per day, with the typical initial range of compoundused being 0.3 to 15 mg/kg/day. The daily does is, in certainembodiments, given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. In the case of a 70 kg adulthuman, the total daily dose will generally be from about 7 mg to about1,400 mg. This dosage regimen may be adjusted to provide the optimaltherapeutic response. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, intracerebral, intraocular, intralesional orsubcutaneous administration.

The compositions comprising compounds of formula I or an embodimentthereof are normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. A typicalformulation is prepared by mixing a compound of the present inventionand a diluent, carrier or excipient. Suitable diluents, carriers andexcipients are well known to those skilled in the art and are describedin detail in, e.g., Ansel, Howard C., et al., Ansel's PharmaceuticalDosage Forms and Drug Delivery Systems. Philadelphia: Lippincott,Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: TheScience and Practice of Pharmacy. Philadelphia: Lippincott, Williams &Wilkins, 2000; and Rowe, Raymond C. Handbook of PharmaceuticalExcipients. Chicago, Pharmaceutical Press, 2005. The formulations mayalso include one or more buffers, stabilizing agents, surfactants,wetting agents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, perfuming agents, flavoring agents, diluents andother known additives to provide an elegant presentation of the drug(i.e., a compound of the present invention or pharmaceutical compositionthereof) or aid in the manufacturing of the pharmaceutical product(i.e., medicament).

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water and the like. The particularcarrier, diluent or excipient used will depend upon the means andpurpose for which a compound of the present invention is being applied.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations can also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine: monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins: chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Aactive pharmaceutical ingredient of the invention (e.g., compound offormula I or an embodiment thereof) can also be entrapped inmicrocapsules prepared, for example, by coacervation techniques or byinterfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philadelphia, Pa.

Sustained-release preparations of a compound of the invention (e.g.,compound of formula I or an embodiment thereof) can be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of formula I or an embodiment thereof, which matrices are inthe form of shaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983),non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater.Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers suchas the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate) andpoly-D-(−)-3-hydroxybutyric acid (EP 133,988A). Sustained releasecompositions also include liposomally entrapped compounds, which can beprepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci.U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A.77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A).Ordinarily, the liposomes are of the small (about 200-800 Angstroms)unilamelar type in which the lipid content is greater than about 30 mol% cholesterol, the selected proportion being adjusted for the optimaltherapy.

The formulations include those suitable for the administration routesdetailed herein. The formulations can conveniently be presented in unitdosage form and can be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philadelphia, Pa. Such methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients.

In general the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers,diluents or excipients or finely divided solid carriers, diluents orexcipients, or both, and then, if necessary, shaping the product. Atypical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. The formulations can beprepared using conventional dissolution and mixing procedures. Forexample, the bulk drug substance (i.e., compound of the presentinvention or stabilized form of the compound (e.g., complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more of the excipientsdescribed above. A compound of the present invention is typicallyformulated into pharmaceutical dosage forms to provide an easilycontrollable dosage of the drug and to enable patient compliance withthe prescribed regimen.

In one example, compounds of formula I or an embodiment thereof may beformulated by mixing at ambient temperature at the appropriate pH, andat the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a galenical administration form. The pHof the formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of formula I (or an embodimentthereof) is formulated in an acetate buffer, at pH 5. In anotherembodiment, the compounds of formula I or an embodiment thereof aresterile. The compound may be stored, for example, as a solid oramorphous composition, as a lyophilized formulation or as an aqueoussolution.

Formulations of a compound of the invention (e.g., compound of formula Ior an embodiment thereof) suitable for oral administration can beprepared as discrete units such as pills, capsules, cachets or tabletseach containing a predetermined amount of a compound of the invention.

Compressed tablets can be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets can bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets canoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs can be prepared for oral use. Formulationsof a compound of the invention (e.g., compound of formula I or anembodiment thereof) intended for oral use can be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients can be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets can be uncoated or can be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax can be employed.

An example of a suitable oral administration form is a tablet containingabout 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250mg, 300 mg and 500 mg of the compound of the invention compounded withabout 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose,about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving the compound, for example5-400 mg, of the invention in a suitable buffer solution, e.g. aphosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride,if desired. The solution may be filtered, e.g., using a 0.2 micronfilter, to remove impurities and contaminants.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientcan be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients can be formulated in a creamwith an oil-in-water cream base. If desired, the aqueous phase of thecream base can include a polyhydric alcohol, i.e., an alcohol having twoor more hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations can desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs.

The oily phase of the emulsions of this invention can be constitutedfrom known ingredients in a known manner. While the phase can comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

In one aspect of topical applications, it is desired to administer aneffective amount of a pharmaceutical composition according to theinvention to target area. e.g., skin surfaces, mucous membranes, and thelike, which are adjacent to peripheral neurons which are to be treated.This amount will generally range from about 0.0001 mg to about 1 g of acompound of the invention per application, depending upon the area to betreated, whether the use is diagnostic, prophylactic or therapeutic, theseverity of the symptoms, and the nature of the topical vehicleemployed. A preferred topical preparation is an ointment, wherein about0.001 to about 50 mg of active ingredient is used per cc of ointmentbase. The pharmaceutical composition can be formulated as transdermalcompositions or transdermal delivery devices (“patches”). Suchcompositions include, for example, a backing, active compound reservoir,a control membrane, liner and contact adhesive. Such transdermal patchesmay be used to provide continuous pulsatile, or on demand delivery ofthe compounds of the present invention as desired.

Aqueous suspensions of a compound of the invention (e.g., compound offormula I or an embodiment thereof) contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinvlpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

Formulations of a compound of the invention (e.g., compound of formula Ior an embodiment thereof) can be in the form of a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension can be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, such as a solution in1,3-butanediol or prepared as a lyophilized powder. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile fixed oilscan conventionally be employed as a solvent or suspending medium. Forthis purpose any bland fixed oil can be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid canlikewise be used in the preparation of injectables.

The amount of active ingredient that can be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans cancontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which can varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion can contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which can contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which can include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia, and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration can be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration can beprepared according to conventional methods and can be delivered withother therapeutic agents such as compounds heretofore used in thetreatment of disorders as described below.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

When the binding target is located in the brain, certain embodiments ofthe invention provide for a compound of formula I (or an embodimentthereof) to traverse the blood-brain barrier. Certain neurodegenerativediseases are associated with an increase in permeability of theblood-brain barrier, such that a compound of formula I (or an embodimentthereof) can be readily introduced to the brain. When the blood-brainbarrier remains intact, several art-known approaches exist fortransporting molecules across it, including, but not limited to,physical methods, lipid-based methods, and receptor and channel-basedmethods.

Physical methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, circumventing the blood-brain barrier entirely, or bycreating openings in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injectioninto the brain (see, e.g., Papanastassiou et al., Gene Therapy9:398-406, 2002), interstitial infusion/convection-enhanced delivery(see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91:2076-2080,1994), and implanting a delivery device in the brain (see, e.g., Gill etal., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, Guildford.

Pharmaceutical). Methods of creating openings in the barrier include,but are not limited to, ultrasound (see, e.g., U.S. Patent PublicationNo. 2002/0038086), osmotic pressure (e.g., by administration ofhypertonic mannitol (Neuwelt, E. A., Implication of the Blood-BrainBarrier and its Manipulation, Volumes 1 and 2, Plenum Press. N.Y.,1989)), and permeabilization by, e.g., bradykinin or permeabilizer A-7(see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and5,686,416).

Lipid-based methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, encapsulating the a compound of formula I (or an embodimentthereof) in liposomes that are coupled to antibody binding fragmentsthat bind to receptors on the vascular endothelium of the blood-brainbarrier (see. e.g., U.S. Patent Application Publication No.2002/0025313), and coating a compound of formula I (or an embodimentthereof) in low-density lipoprotein particles (see, e.g., U.S. PatentApplication Publication No. 2004/0204354) or apolipoprotein E (see,e.g., U.S. Patent Application Publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of formulaI (or an embodiment thereof) across the blood-brain barrier include, butare not limited to, using glucocorticoid blockers to increasepermeability of the blood-brain barrier (see, e.g., U.S. PatentApplication Publication Nos. 2002/0065259, 2003/0162695, and2005/0124533); activating to potassium channels (see, e.g., U.S. PatentApplication Publication No. 2005/0089473), inhibiting ABC drugtransporters (see, e.g., U.S. Patent Application Publication No.2003/0073713); coating a compound of formula I (or an embodimentthereof) with a transferrin and modulating activity of the one or moretransferrin receptors (see, e.g., U.S. Patent Application PublicationNo. 2003/0129186), and cationizing the antibodies (see, e.g., U.S. Pat.No. 5,004,697).

For intracerebral use, in certain embodiments, the compounds can beadministered continuously by infusion into the fluid reservoirs of theCNS, although bolus injection may be acceptable. The inhibitors can beadministered into the ventricles of the brain or otherwise introducedinto the CNS or spinal fluid. Administration can be performed by use ofan indwelling catheter and a continuous administration means such as apump, or it can be administered by implantation, e.g., intracerebralimplantation of a sustained-release vehicle. More specifically, theinhibitors can be injected through chronically implanted cannulas orchronically infused with the help of osmotic minipumps. Subcutaneouspumps are available that deliver proteins through a small tubing to thecerebral ventricles. Highly sophisticated pumps can be refilled throughthe skin and their delivery rate can be set without surgicalintervention. Examples of suitable administration protocols and deliverysystems involving a subcutaneous pump device or continuousintracerebroventricular infusion through a totally implanted drugdelivery system are those used for the administration of dopamine,dopamine agonists, and cholinergic agonists to Alzheimer's diseasepatients and animal models for Parkinson's disease, as described byHarbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al.,Mov. Disord. 2: 143, 1987.

A compound of formula I (or an embodiment thereof) used in the inventionare formulated, dosed, and administered in a fashion consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. A compound of formula I (or anembodiment thereof) need not be, but is optionally formulated with oneor more agent currently used to prevent or treat the disorder inquestion. The effective amount of such other agents depends on theamount of a compound of the invention present in the formulation, thetype of disorder or treatment, and other factors discussed above.

These are generally used in the same dosages and with administrationroutes as described herein, or about from 1 to 99% of the dosagesdescribed herein, or in any dosage and by any route that isempirically/clinically determined to be appropriate.

For the prevention or treatment of disease, the appropriate dosage of acompound of formula I (or an embodiment thereof) (when used alone or incombination with other agents) will depend on the type of disease to betreated, the properties of the compound, the severity and course of thedisease, whether the compound is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the compound, and the discretion of the attendingphysician. The compound is suitably administered to the patient at onetime or over a series of treatments. Depending on the type and severityof the disease, about 1 μg/kg to 15 mg/kg (e.g., 0.1 mg/kg-10 mg/kg) ofcompound can be an initial candidate dosage for administration to thepatient, whether, for example, by one or more separate administrations,or by continuous infusion. One typical daily dosage might range fromabout 1 μg kg to 100 mg/kg or more, depending on the factors mentionedabove. For repeated administrations over several days or longer,depending on the condition, the treatment would generally be sustaineduntil a desired suppression of disease symptoms occurs. One exemplarydosage of a compound of formula I (or an embodiment thereof) would be inthe range from about 0.05 mg/kg to about 10 mg/kg. Thus, one or moredoses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg (or anycombination thereof) may be administered to the patient. Such doses maybe administered intermittently, e.g., every week or every three weeks(e.g., such that the patient receives from about two to about twenty,or, e.g., about six doses of the antibody). An initial higher loadingdose, followed by one or more lower doses may be administered. Anexemplary dosing regimen comprises administering an initial loading doseof about 4 mg/kg, followed by a weekly maintenance dose of about 2 mg kgof the compound. However, other dosage regimens may be useful. Theprogress of this therapy is easily monitored by conventional techniquesand assays.

Other typical daily dosages might range from, for example, about 1 g/kgto up to 100 mg/kg or more (e.g., about 1 μg kg to 1 mg/kg, about 1μg/kg to about 5 mg/kg, about 1 mg kg to 10 mg/kg, about 5 mg/kg toabout 200 mg/kg, about 50 mg/kg to about 150 mg/mg, about 100 mg/kg toabout 500 mg/kg, about 100 mg/kg to about 400 mg/kg, and about 200 mg/kgto about 400 mg/kg), depending on the factors mentioned above.Typically, the clinician will administer a compound until a dosage isreached that results in improvement in or, optimally, elimination of,one or more symptoms of the treated disease or condition. The progressof this therapy is easily monitored by conventional assays. One or moreagent provided herein may be administered together or at different times(e.g., one agent is administered prior to the administration of a secondagent). One or more agent may be administered to a subject usingdifferent techniques (e.g., one agent may be administered orally, whilea second agent is administered via intramuscular injection orintranasally). One or more agent may be administered such that the oneor more agent has a pharmacologic effect in a subject at the same time.Alternatively, one or more agent may be administered, such that thepharmacological activity of the first administered agent is expiredprior the administration of one or more secondarily administered agents(e.g., 1, 2, 3, or 4 secondarily administered agents).

C. Indications and Methods of Treatment

The compounds of the invention modulate, preferably inhibit, ion fluxthrough a voltage-dependent sodium channel in a mammal, (e.g, a human).Any such modulation, whether it be partial or complete inhibition orprevention of ion flux, is sometimes referred to herein as “blocking”and corresponding compounds as “blockers” or “inhibitors”. In general,the compounds of the invention modulate the activity of a sodium channeldownwards by inhibiting the voltage-dependent activity of the sodiumchannel, and/or reduce or prevent sodium ion flux across a cell membraneby preventing sodium channel activity such as ion flux.

Accordingly, the compounds of the invention are sodium channel blockersand are therefore useful for treating diseases and conditions inmammals, for example humans, and other organisms, including all thosediseases and conditions which are the result of aberrantvoltage-dependent sodium channel biological activity or which may beameliorated by modulation of voltage-dependent sodium channel biologicalactivity. In particular, the compounds of the invention, i.e., thecompounds of formula (I) and embodiments and (or stereoisomers,geometric isomers, tautomers, solvates, metabolites, isotopes,pharmaceutically acceptable salts, or prodrugs thereof), are useful fortreating diseases and conditions in mammals, for example humans, whichare the result of aberrant voltage-dependent NaV1.7 biological activityor which may be ameliorated by the modulation, preferably theinhibition, of NaV1.7 biological activity. In certain aspects, thecompounds of the invention selectively inhibit NaV1.7 over NaV1.5.

As defined herein, a sodium channel-mediated disease or condition refersto a disease or condition in a mammal, preferably a human, which isameliorated upon modulation of the sodium channel and includes, but isnot limited to, pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease: cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus: neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome.

In one aspect, the present invention relates to compounds,pharmaceutical compositions and methods of using the compounds andpharmaceutical compositions for the treatment of sodium channel-mediateddiseases in mammals, preferably humans and preferably diseases andconditions related to pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome, by administering to a mammal, for examplea human, in need of such treatment an effective amount of a sodiumchannel blocker modulating, especially inhibiting, agent.

A sodium channel-mediated disease or condition also includes painassociated with HIV, HIV treatment induced neuropathy, trigeminalneuralgia, glossopharyngeal neuralgia, neuropathy secondary tometastatic infiltration, adiposis dolorosa, thalamic lesions,hypertension, autoimmune disease, asthma, drug addiction (e.g., opiate,benzodiazepine, amphetamine, cocaine, alcohol, butane inhalation),Alzheimer, dementia, age-related memory impairment, Korsakoff syndrome,restenosis, urinary dysfunction, incontinence, Parkinson's disease,cerebrovascular ischemia, neurosis, gastrointestinal disease, sicklecell anemia, transplant rejection, heart failure, myocardial infarction,reperfusion injury, intermittant claudication, angina, convulsion,respiratory disorders, cerebral or myocardial ischemias, long-QTsyndrome, Catecholeminergic polymorphic ventricular tachycardia,ophthalmic diseases, spasticity, spastic paraplegia, myopathies,myasthenia gravis, paramyotonia congentia, hyperkalemic periodicparalysis, hypokalemic periodic paralysis, alopecia, anxiety disorders,psychotic disorders, mania, paranoia, seasonal affective disorder, panicdisorder, obsessive compulsive disorder (OCD), phobias, autism,Aspergers Syndrome, Retts syndrome, disintegrative disorder, attentiondeficit disorder, aggressivity, impulse control disorders, thrombosis,pre clampsia, congestive cardiac failure, cardiac arrest, Freidrich'sataxia, Spinocerebellear ataxia, myelopathy, radiculopathy, systemiclupus erythamatosis, granulomatous disease, olivo-ponto-cerebellaratrophy, spinocerebellar ataxia, episodic ataxia, myokymia, progressivepallidal atrophy, progressive supranuclear palsy and spasticity,traumatic brain injury, cerebral oedema, hydrocephalus injury, spinalcord injury, anorexia nervosa, bulimia, Prader-Willi syndrome, obesity,optic neuritis, cataract, retinal haemorrhage, ischaemic retinopathy,retinitis pigmentosa, acute and chronic glaucoma, macular degeneration,retinal artery occlusion, Chorea, Huntington's chorea, cerebral edema,proctitis, post-herpetic neuralgia, eudynia, heat sensitivity,sarcoidosis, irritable bowel syndrome, Tourette syndrome, Lesch-NyhanSyndrome, Brugado syndrome, Liddle syndrome, Crohns disease, multiplesclerosis and the pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), disseminated sclerosis, diabeticneuropathy, peripheral neuropathy, charcot marie tooth syndrome,arthritic, rheumatoid arthritis, osteoarthritis, chondrocalcinosis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,myotonic dystrophy, muscular dystrophy, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, mental handicap,hypothyroidism, bipolar depression, anxiety, schizophrenia, sodiumchannel toxin related illnesses, familial erythromelalgia, primaryerythromelalgia, rectal pain, cancer, epilepsy, partial and generaltonic seizures, febrile seizures, absence seizures (petit mal),myoclonic seizures, atonic seizures, clonic seizures, Lennox Gastaut,West Syndome (infantile spasms), multiresistant seizures, seizureprophylaxis (anti-epileptogenic), familial Mediterranean fever syndrome,gout, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotectionunder ischaemic conditions caused by stroke or neural trauma,tachy-arrhythmias, atrial fibrillation and ventricular fibrillation andas a general or local anaesthetic.

As used herein, the term “pain” refers to all categories of pain and isrecognized to include, but is not limited to, neuropathic pain,inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain,orofacial pain, burn pain, burning mouth syndrome, somatic pain,visceral pain, myofacial pain, dental pain, cancer pain, chemotherapypain, trauma pain, surgical pain, post-surgical pain, childbirth pain,labor pain, chronic regional pain syndrome (CRPS), reflex sympatheticdystrophy, brachial plexus avulsion, neurogenic bladder, acute pain(e.g., musculoskeletal and post-operative pain), chronic pain,persistent pain, peripherally mediated pain, centrally mediated pain,chronic headache, migraine headache, familial hemiplegic migraine,conditions associated with cephalic pain, sinus headache, tensionheadache, phantom limb pain, peripheral nerve injury, pain followingstroke, thalamic lesions, radiculopathy. HIV pain, post-herpetic painnon-cardiac chest pain, irritable bowel syndrome and pain associatedwith bowel disorders and dyspepsia, and combinations thereof.

Furthermore, sodium channel blockers have clinical uses in addition topain. The present invention therefore also relates to compounds,pharmaceutical compositions and methods of using the compounds andpharmaceutical compositions for the treatment of diseases or conditionssuch as cancer and pruritus (itch).

Pruritus, commonly known as itch, is a common dermatological condition.While the exact causes of pruritus are complex and incompletelyunderstood, there has long been evidence that itch involves sensoryneurons, especially C fibers, similar to those that mediate pain(Schmelz, M., et al., J. Neurosci. (1997), 17: 8003-8). In particular,it is believed that sodium influx through voltage-gated sodium channelsis essential for the propagation of itch sensation from the skin.Transmission of the itch impulses results in the unpleasant sensationthat elicits the desire or reflex to scratch.

Multiple causes and electrical pathways for eliciting itch are known. Inhumans, pruritis can be elicited by histamine or PAR-2 agonists such asmucunain that activate distinct populations of C fibers (Namer, B., etal., J. Neurophysiol. (2008), 100: 2062-9). A variety of neurotrophicpeptides are known to mediate itch in animal models (Wang, H., andYosipovitch, G., International Journal of Dermatology (2010), 49: 1-11).Itch can also be elicited by opioids, evidence of distinct pharmacologyfrom that of pain responses.

There exists a complex interaction between itch and pain responses thatarises in part from the overlapping sensory input from the skin (Ikoma,A., et al., Arch. Dermatol. (2003), 139: 1475-8) and also from thediverse etiology of both pain and pruritis. Pain responses canexacerbate itching by enhancing central sensitization or lead toinhibition of painful scratching. Particularly severe forms of chronicitch occur when pain responses are absent, as in the case ofpost-herpetic itch (Oaklander. A. L., et al., Pain (2002), 96: 9-12).

The compounds of the invention can also be useful for treating pruritus.The rationale for treating itch with inhibitors of voltage-gated sodiumchannels, especially NaV1.7, is as follows: The propagation ofelectrical activity in the C fibers that sense pruritinergic stimulantsrequires sodium entry through voltage-gated sodium channels.

NaV1.7 is expressed in the C fibers and kerotinocytes in human skin(Zhao, P., et al., Pain (2008), 139: 90-105).

A gain of function mutation of NaV1.7 (L858F) that causeserythromelalgia also causes chronic itch (Li, Y., et al., Clinical andExperimental Dermatology (2009), 34: e313-e4).

Chronic itch can be alleviated with treatment by sodium channelblockers, such as the local anesthetic lidocaine (Oaklander. A. L., etal., Pain (2002), 96: 9-12; Villamil, A. G., et al., The AmericanJournal of Medicine (2005), 118: 1160-3). In these reports, lidocainewas effective when administered either intravenously or topically (aLidoderm patch). Lidocaine can have multiple activities at the plasmaconcentrations achieved when administered systemically, but whenadministered topically, the plasma concentrations are only about 1 μM(Center for Drug Evaluation and Research NDA 20-612). At theseconcentrations, lidocaine is selective for sodium channel block andinhibits spontaneous electrical activity in C fibers and pain responsesin animal models (Xiao, W. H., and Bennett, G. J., Pain (2008), 137:218-28). The types of itch or skin irritation, include, but are notlimited to:

psoriatic pruritus, itch due to hemodyalisis, aguagenic pruritus, anditching caused by skin disorders (e.g., contact dermatitis), systemicdisorders, neuropathy, psychogenic factors or a mixture thereof:

itch caused by allergic reactions, insect bites, hypersensitivity (e.g.,dry skin, acne, eczema, psoriasis), inflammatory conditions or injury:

itch associated with vulvar vestibulitis; and

skin irritation or inflammatory effect from administration of anothertherapeutic such as, for example, antibiotics, antivirals andantihistamines.

The compounds of the invention are also useful in treating certaincancers, such as hormone sensitive cancers, such as prostate cancer(adenocarcinoma), breast cancer, ovarian cancer, testicular cancer andthyroid neoplasia, in a mammal, preferably a human. The voltage gatedsodium channels have been demonstrated to be expressed in prostate andbreast cancer cells. Up-regulation of neonatal NaV1.5 occurs as anintegral part of the metastatic process in human breast cancer and couldserve both as a novel marker of the metastatic phenotype and atherapeutic target (Clin. Cancer Res. (2005), August 1; 11(15): 5381-9).Functional expression of voltage-gated sodium channel alpha-subunits,specifically NaV1.7, is associated with strong metastatic potential inprostate cancer (CaP) in vitro. Voltage-gated sodium channelalpha-subunits immunostaining, using antibodies specific to the sodiumchannel alpha subunit was evident in prostatic tissues and markedlystronger in CaP vs non-CaP patients (Prostate Cancer Prostatic Dis.,2005; 8(3):266-73). See also Diss, J. K. J., et al., Mol. Cell.Neurosci. (2008), 37:537-547 and Kis-Toth, K., et al., The Journal ofImmunology (2011), 187:1273-1280.

In consideration of the above, in one embodiment, the present inventionprovides a method for treating a mammal for, or protecting a mammal fromdeveloping, a sodium channel-mediated disease, especially pain,comprising administering to the mammal, especially a human, in needthereof, a therapeutically effective amount of a compound of theinvention or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention wherein the compoundmodulates the activity of one or more voltage-dependent sodium channels.

In another embodiment of the invention is a method of treating a diseaseor a condition in a mammal, preferably a human, wherein the disease orcondition is selected from the group consisting of pain, depression,cardiovascular diseases, respiratory diseases, and psychiatric diseases,and combinations thereof, and wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of anembodiment of a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

One embodiment of this embodiment is wherein the disease or condition isselected from the group consisting of acute pain, chronic pain,neuropathic pain, inflammatory pain, visceral pain, cancer pain,chemotherapy pain, trauma pain, surgical pain, post surgical pain,childbirth pain, labor pain, neurogenic bladder, ulcerative colitis,persistent pain, peripherally mediated pain, centrally mediated pain,chronic headache, migraine headache, sinus headache, tension headache,phantom limb pain, peripheral nerve injury, and combinations thereof.

Another embodiment of this embodiment is wherein the disease orcondition is selected from the group consisting of pain associated withHIV, HIV treatment induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritablebowel syndrome, Crohns disease, pain associated with multiple sclerosis(MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy,peripheral neuropathy, arthritic, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxin related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscaused by stroke or neural trauma, tachy arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is a method of treating, but notpreventing, pain in a mammal, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

One embodiment of this embodiment is a method wherein the pain isselected from the group consisting of neuropathic pain, inflammatorypain, visceral pain, cancer pain, chemotherapy pain, trauma pain,surgical pain, post surgical pain, childbirth pain, labor pain, dentalpain, chronic pain, persistent pain, peripherally mediated pain,centrally mediated pain, chronic headache, migraine headache, sinusheadache, tension headache, phantom limb pain, peripheral nerve injury,trigeminal neuralgia, post herpetic neuralgia, eudynia, familialerythromelalgia, primary erythromelalgia, familial rectal pain orfibromyalgia, and combinations thereof.

Another embodiment of this embodiment is a method wherein the pain isassociated with a disease or condition selected from HIV, HIV treatmentinduced neuropathy, heat sensitivity, tosarcoidosis, irritable bowelsyndrome, Crohns disease, multiple sclerosis, amyotrophic lateralsclerosis, diabetic neuropathy, peripheral neuropathy, rheumatoidarthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia,myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses,neurogenic bladder, ulcerative colitis, cancer, epilepsy, partial andgeneral tonic seizures, restless leg syndrome, arrhythmias, ischaemicconditions caused by stroke or neural trauma, tachy arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is the method of treating pain in amammal, preferably a human, by the inhibition of ion flux through avoltage dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal in need thereof a therapeuticallyeffective amount of an embodiment of a compound of the invention, as setforth above, as a stereoisomer, enantiomer or tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer or tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, and a pharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating pruritusin a mammal, preferably a human, wherein the method comprisesadministering to the mammal in need thereof a therapeutically effectiveamount of an embodiment of a compound of the invention, as set forthabove, as a stereoisomer, enantiomer or tautomer thereof or mixturesthereof, or a pharmaceutically acceptable salt, solvate or prodrugthereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of the invention, as set forth above, asa stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating cancer ina mammal, preferably a human, wherein the method comprises administeringto the mammal in need thereof a therapeutically effective amount of anembodiment of a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of decreasing ion fluxthrough a voltage dependent sodium channel in a cell in a mammal,wherein the method comprises contacting the cell with an embodiment of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof.

Another embodiment of the invention is the method of selectivelyinhibiting a first voltage-gated sodium channel over a secondvoltage-gated sodium channel in a mammal, wherein the method comprisesadministering to the mammal an inhibitory amount of a compound offormula (I), or an embodiment of a compound of formula (I).

Another embodiment of the invention is the method of selectivelyinhibiting NaV1.7 in a mammal or a mammalian cell as compared to NaV1.5,wherein the method comprises administering to the mammal in need thereofan inhibitory amount of a compound of formula (I) or an embodiment of anembodiment thereof.

For each of the above embodiments described related to treating diseasesand conditions in a mammal, the present invention also contemplatesrelatedly a compound of formula I or an embodiment thereof for the useas a medicament in the treatment of such diseases and conditions.

For each of the above embodiments described related to treating diseasesand conditions in a mammal, the present invention also contemplatesrelatedly the use of a compound of formula I or an embodiment thereoffor the manufacture of a medicament for the treatment of such diseasesand conditions.

Another embodiment of the invention is a method of using the compoundsof formula (I) as standards or controls in in vitro or in vivo assays indetermining the efficacy of test compounds in modulatingvoltage-dependent sodium channels.

In another embodiment of the invention, the compounds of formula (I) areisotopically-labeled by having one or more atoms therein replaced by anatom having a different atomic mass or mass number. Suchisotopically-labeled (i.e., radiolabelled) compounds of formula (I) areconsidered to be within the scope of this invention. Examples ofisotopes that can be incorporated into the compounds of formula (I)include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl,¹²³I, and ¹²⁵I, respectively. These isotopically-labeled compounds wouldbe useful to help determine or measure the effectiveness of thecompounds, by characterizing, for example, the site or mode of action onthe sodium channels, or binding affinity to pharmacologically importantsite of action on the sodium channels, particularly NaV1.7. Certainisotopically-labeled compounds of formula (I), for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Testing Compounds

The assessment of the compounds of the invention in mediating,especially inhibiting, the sodium channel ion flux can be determinedusing the assays described hereinbelow. Alternatively, the assessment ofthe compounds in treating conditions and diseases in humans may beestablished in industry standard animal models for demonstrating theefficacy of compounds in treating pain. Animal models of humanneuropathic pain conditions have been developed that result inreproducible sensory deficits (allodynia, hyperalgesia, and spontaneouspain) over a sustained period of time that can be evaluated by sensorytesting. By establishing the degree of mechanical, chemical, andtemperature induced allodynia and hyperalgesia present, severalphysiopathological conditions observed in humans can be modeled allowingthe evaluation of pharmacotherapies.

In rat models of peripheral nerve injury, ectopic activity in theinjured nerve corresponds to the behavioural signs of pain. In thesemodels, intravenous application of the sodium channel blocker and localanesthetic lidocaine can suppress the ectopic activity and reverse thetactile allodynia at concentrations that do not affect general behaviourand motor function (Mao, J. and Chen, L. L. Pain (2000), 87:7-17).Allometric scaling of the doses effective in these rat models,translates into doses similar to those shown to be efficacious in humans(Tanelian, D. L. and Brose, W. G., Anesthesiology (1991),74(5):949-951). Furthermore, Lidoderm, lidocaine applied in the form ofa dermal patch, is currently an FDA approved treatment for post-herpeticneuralgia (Devers, A. and Glaler, B. S., Clin. J. Pain (2000),16(3):205-8).

The present invention readily affords many different means foridentification of sodium channel modulating agents that are useful astherapeutic agents. Identification of modulators of sodium channel canbe assessed using a variety of in vitro and in vivo assays, e.g.,measuring to current, measuring membrane potential, measuring ion flux,(e.g., sodium or guanidinium), measuring sodium concentration, measuringsecond messengers and transcription levels, and using e.g.,voltage-sensitive dyes, radioactive tracers, and patch-clampelectrophysiology.

One such protocol involves the screening of chemical agents for abilityto modulate the activity of a sodium channel thereby identifying it as amodulating agent.

A typical assay described in Bean et al., J. General Physiology (1983),83:613-642, and Leuwer, M., et al., Br. J. Pharmacol (2004),141(1):47-54, uses patch-clamp techniques to study the behaviour ofchannels. Such techniques are known to those skilled in the art, and maybe developed, using current technologies, into low or medium throughputassays for evaluating compounds for their ability to modulate sodiumchannel behaviour.

Throughput of test compounds is an important consideration in the choiceof screening assay to be used. In some strategies, where hundreds ofthousands of compounds are to be tested, it is not desirable to use lowthroughput means. In other cases, however, low throughput issatisfactory to identify important differences between a limited numberof compounds. Often it will be necessary to combine assay types toidentify specific sodium channel modulating compounds.

Electrophysiological assays using patch clamp techniques is accepted asa gold standard for detailed characterization of sodium channel compoundinteractions, and as described in Bean et al., op. cit. and Leuwer, M.,et al., op. cit. There is a manual low-throughput screening (LTS) methodwhich can compare 2-10 compounds per day; a recently developed systemfor automated medium-throughput screening (MTS) at 20-50 patches (i.e.compounds) per day; and a technology from Molecular Devices Corporation(Sunnyvale, Calif.) which permits automated high-throughput screening(HTS) at 1000-3000 patches (i.e. compounds) per day.

One automated patch-clamp system utilizes planar electrode technology toaccelerate the rate of drug discovery. Planar electrodes are capable ofachieving high-resistance, cells-attached seals followed by stable,low-noise whole-cell recordings that are comparable to conventionalrecordings. A suitable instrument is the PatchXpress 7000A (AxonInstruments Inc, Union City, Calif.). A variety of cell lines andculture techniques, which include adherent cells as well as cellsgrowing spontaneously in suspension are ranked for seal success rate andstability. Immortalized cells (e.g. HEK and CHO) stably expressing highlevels of the relevant sodium ion channel can be adapted intohigh-density suspension cultures.

Other assays can be selected which allow the investigator to identifycompounds which block specific states of the channel, such as the openstate, closed state or the resting state, or which block transition fromopen to closed, closed to resting or resting to open. Those skilled inthe art are generally familiar with such assays.

Binding assays are also available. Designs include traditionalradioactive filter based binding assays or the confocal basedfluorescent system available from Evotec OAI group of companies(Hamburg, Germany), both of which are HTS.

Radioactive flux assays can also be used. In this assay, channels arestimulated to open with veratridine or aconitine and held in astabilized open state with a toxin, and channel blockers are identifiedby their ability to prevent ion influx. The assay can use radioactive22[Na] and 14[C] guanidinium ions as tracers. FlashPlate & Cytostar-Tplates in living cells avoids separation steps and are suitable for HTS.Scintillation plate technology has also advanced this method to HTSsuitability. Because of the functional aspects of the assay, theinformation content is reasonably good.

Yet another format measures the redistribution of membrane potentialusing the FLIPR system membrane potential kit (HTS) available fromMolecular Dynamics (a division of Amersham Biosciences, Piscataway,N.J.). This method is limited to slow membrane potential changes. Someproblems may result from the fluorescent background of compounds. Testcompounds may also directly influence the fluidity of the cell membraneand lead to an increase in intracellular dye concentrations. Still,because of the functional aspects of the assay, the information contentis reasonably good.

Sodium dyes can be used to measure the rate or amount of sodium ioninflux through a channel. This type of assay provides a very highinformation content regarding potential channel blockers. The assay isfunctional and would measure Na+ influx directly. CoroNa Red. SBFIand/or sodium green (Molecular Probes, Inc. Eugene Oreg.) can be used tomeasure Na influx; all are Na responsive dyes. They can be used incombination with the FLIPR instrument. The use of these dyes in a screenhas not been previously described in the literature. Calcium dyes mayalso have potential in this format.

In another assay, FRET based voltage sensors are used to measure theability of a test compound to directly block Na influx. Commerciallyavailable HTS systems include the VIPR™ II FRET system (LifeTechnologies, or Aurora Biosciences Corporation, San Diego, Calif., adivision of Vertex Pharmaceuticals, Inc.) which may be used inconjunction with FRET dyes, also available from Aurora Biosciences. Thisassay measures sub-second responses to voltage changes. There is norequirement for a modifier of channel function. The assay measuresdepolarization and hyperpolarizations, and provides ratiometric outputsfor quantification. A somewhat less expensive MTS version of this assayemploys the FLEXstation™ (Molecular Devices Corporation) in conjunctionwith FRET dyes from Aurora Biosciences. Other methods of testing thecompounds disclosed herein are also readily known and available to thoseskilled in the art.

Modulating agents so identified are then tested in a variety of in vivomodels so as to determine if they alleviate pain, especially chronicpain or other conditions such as cancer and pruritus (itch) with minimaladverse events. The assays described below in the Biological AssaysSection are useful in assessing the biological activity of the instantcompounds.

Typically, the efficacy of a compound of the invention is expressed byits IC50 value (“Inhibitory Concentration—50%”), which is the measure ofthe amount of compound required to achieve 50% inhibition of theactivity of the target sodium channel over a specific time period. Forexample, representative compounds of the present invention havedemonstrated IC50's ranging from less than 100 nanomolar to less than 10micromolar in the patch voltage clamp NaV1.7 electrophysiology assaydescribed herein.

In another aspect of the invention, the compounds of the invention canbe used in in vitro or in vivo studies as exemplary agents forcomparative purposes to find other compounds also useful in treatmentof, or protection from, the various diseases disclosed herein.

Another aspect of the invention relates to inhibiting NaV1.1. NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 activity,preferably NaV1.7 activity, in a biological sample or a mammal,preferably a human, which method comprises administering to the mammal,preferably a human, or contacting said biological sample with a compoundof formula (I) or a pharmaceutical composition comprising a compound offormula (I). The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5. NaV1.6, NaV1.7,NaV1.8, or NaV1.9 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumion channels in biological and pathological phenomena; and thecomparative evaluation of new sodium ion channel inhibitors.

The compounds of the invention (or stereoisomers, geometric isomers,tautomers, solvates, metabolites, isotopes, pharmaceutically acceptablesalts, or prodrugs thereof) and/or the pharmaceutical compositionsdescribed herein which comprise a pharmaceutically acceptable excipientand one or more compounds of the invention, can be used in thepreparation of a medicament for the treatment of sodium channel-mediateddisease or condition in a mammal.

E. Combination Therapy

The compounds of the invention may be usefully combined with one or moreother compounds of the invention or one or more other therapeutic agentor as any combination thereof, in the treatment of sodiumchannel-mediated diseases and conditions. For example, a compound of theinvention may be administered simultaneously, sequentially or separatelyin combination with other therapeutic agents, including, but not limitedto:

opiates analgesics, e.g., morphine, heroin, cocaine, oxymorphine,levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine,propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone,meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine,butorphanol, nalbuphine and pentazocine;

non-opiate analgesics, e.g., acetomeniphen, salicylates (e.g., aspirin):

nonsteroidal antiinflammatory drugs (NSAIDs), e.g., ibuprofen, naproxen,fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal, etodolac,fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin,ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam,nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetinand zomepirac;

anticonvulsants, e.g., carbamazepine, oxcarbazepine, lamotrigine,valproate, topiramate, gabapentin and pregabalin;

antidepressants such as tricyclic antidepressants, e.g., amitriptyline,clomipramine, despramine, imipramine and nortriptyline;

COX-2 selective inhibitors, e.g., celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, and lumiracoxib;

alpha-adrenergics, e.g., doxazosin, tamsulosin, clonidine, guanfacine,dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;

barbiturate sedatives, e.g., amobarbital, aprobarbital, butabarbital,butabital, mephobarbital, metharbital, methohexital, pentobarbital,phenobartital, secobarbital, talbutal, theamylal and thiopental;

tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1antagonist, e.g., (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637),5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S):

coal-tar analgesics, in particular paracetamol:

serotonin reuptake inhibitors, e.g., paroxetine, sertraline,norfluoxetine (fluoxetine desmethyl metabolite), metabolitedemethylsertraline, ′3 fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,l-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine, trazodone and fluoxetine; noradrenaline(norepinephrine) reuptake inhibitors, e.g., maprotiline, lofepramine,mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserin,buproprion, buproprion metabolite hydroxybuproprion, nomifensine andviloxazine (Vivalan®)), especially a selective noradrenaline reuptakeinhibitor such as reboxetine, in particular (S,S)-reboxetine, andvenlafaxine duloxetine neuroleptics sedative/anxiolytics;

dual serotonin-noradrenaline reuptake inhibitors, such as venlafaxine,venlafaxine metabolite O-desmethylvenlafaxine, clomipramine,clomipramine metabolite desmethylclomipramine, duloxetine, milnacipranand imipramine;

acetylcholinesterase inhibitors such as donepezil; 5-HT3 antagonistssuch as ondansetron;

metabotropic glutamate receptor (mGluR) antagonists;

local anaesthetic such as mexiletine and lidocaine:

corticosteroid such as dexamethasone:

antiarrhythimics, e.g., mexiletine and phenytoin;

muscarinic antagonists, e.g., tolterodine, propiverine, tropsium tchloride, darifenacin, solifenacin, temiverine and ipratropium;

cannabinoids;

vanilloid receptor agonists (e.g., resinferatoxin) or antagonists (e.g.,capsazepine); sedatives, e.g., glutethimide, meprobamate, methaqualone,and dichloralphenazone; anxiolytics such as benzodiazepines,

antidepressants such as mirtazapine,

topical agents (e.g., lidocaine, capsacin and resiniferotoxin);

muscle relaxants such as benzodiazepines, baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenadine;

anti-histamines or H1 antagonists;

NMDA receptor antagonists:

5-HT receptor agonists/antagonists;

PDEV inhibitors;

Tramadol®:

cholinergic (nicotinc) analgesics;

alpha-2-delta ligands;

prostaglandin E2 subtype antagonists;

leukotriene B4 antagonists;

5-lipoxygenase inhibitors; and

5-HT3 antagonists.

Sodium channel-mediated diseases and conditions that may be treatedand/or prevented using such combinations include but not limited to,pain, central and peripherally mediated, acute, chronic, neuropathic aswell as other diseases with associated pain and other central nervousdisorders such as epilepsy, anxiety, depression and bipolar disease; orcardiovascular disorders such as arrhythmias, atrial fibrillation andventricular fibrillation; neuromuscular disorders such as restless legsyndrome and muscle paralysis or tetanus; neuroprotection againststroke, neural trauma and multiple sclerosis, and channelopathies suchas erythromyalgia and familial rectal pain syndrome.

As used herein “combination” refers to any mixture or permutation of oneor more compounds of the invention and one or more other compounds ofthe invention or one or more additional therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include simultaneous orsequentially delivery of a compound of the invention with one or moretherapeutic agents. Unless the context makes clear otherwise,“combination” may include dosage forms of a compound of the inventionwith another therapeutic agent. Unless the context makes clearotherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include formulations ofa compound of the invention with another therapeutic agent. Dosageforms, routes of administration and pharmaceutical compositions include,but are not limited to, those described herein.

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

These examples serve to provide guidance to a skilled artisan to prepareand use the compounds, compositions and methods of the invention. Whileparticular embodiment of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinventions.

The chemical reactions in the examples described can be readily adaptedto prepare a number of other compounds of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-exemplified compounds according to the invention can be successfullyperformed by modifications apparent to those skilled in the art, forexample, by appropriately protecting interfering group, by utilizingother suitable reagents known in the art, for example, by appropriatelyprotecting interfering groups by utilizing other suitable reagents knownin the art other than those described, and/or by making routinemodifications of reaction conditions.

In the examples below, unless otherwise indicated all temperatures areset forth in degrees Celsius. Commercially available reagents werepurchased from suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge and were used without further purification unlessotherwise indicated. The reactions set forth below were done generallyunder a positive pressure of nitrogen or argon or with a drying tube(unless otherwise stated) in anhydrous solvents, and the reaction flaskswere typically fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. ¹H NMR spectra were obtained in deuterated CDCl₃, d₆-DMSO,CH₃OD or d₆-acetone solvent solutions (reported in ppm) using ortrimethylsilane (TMS) or residual non-deuterated solvent peaks as thereference standard. When peak multiplicities are reported, the followingabbreviates are used: s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet, br (broadened), dd (doublet of doublets), dt(doublet of triplets). Coupling constants, when given, ar reported in Hz(Hertz).

All abbreviations used to describe reagents, reaction conditions orequipment are intended to be consistent with the definitions set forthin the following list of Abbreviations. The chemical names of discretecompounds of the invention were typically obtained using the structurenaming feature of ChemDraw naming program.

ABBREVIATIONS

-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   HPLC High Pressure Liquid Chromatography-   LCMS Liquid Chromatography Mass Spectrometry-   RT Retention time

EXAMPLES Example 1 Synthesis of(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

To a stirred solution of4-(adamantan-1-ylmethoxyl)-5-cyclopropyl-2-fluorobenzoic acid (0.35 g,1.00 mmol) in acetonitrile (20 mL) was addedO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) (0.64 g, 2.00 mmol), hydroxybenzotriazole (HOBt) (0.20 g, 1.50mmol) and N,N-diisopropylethylamine (1.0 mL, 5.74 mL). After 10 minutes,(S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride (0.30 g, 1.44mmol) was added and stirring was continued at ambient temperature for 20hours. Diluted with ethyl acetate (200 mL), and washed with saturatedsodium bicarbonate solution (20 mL×3), water and brine; dried overanhydrous sodium sulfate and concentrated in vacuo. Purification of theresidue by column chromatography (10% ethyl acetate in hexanes) toprovide the title compound as a colorless foam (0.34 g, 68%): ¹H NMR(300 MHz, CDCl₃) δ 6.92 (d, J=8.1 Hz, 1H), 6.47 (d, J=11.7 Hz, 1H),4.49-4.43 (m, 1H), 3.54-3.33 (m, 4H), 2.30-2.21 (m, 1H), 2.05-1.63 (m,17H), 1.45 (s, 9H), 0.89-0.78 (m, 4H), 0.62-0.51 (m, 2H),

Step 2. Preparation of(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

To a solution of (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-pyrrolidine-2-carboxylate(0.34 g, 0.68 mmol) in dichloromethane (10 mL) was added trifluoroaceticacid (5 mL). The mixture was stirred at ambient temperature for 4 hoursand then concentrated in vacuo. The residue was washed with hexanes toprovide the title compound as colorless solid (0.28 g, 92%): ¹H NMR (300MHz, CDCl₃) δ 6.95 (d, J=8.1 Hz, 1H), 6.51 (d, J=12.0 Hz, 1H), 4.75-4.69(m, 1H), 3.55-3.37 (m, 4H), 2.55-2.40 (m, 1H), 2.19-1.64 (m, 17H),0.96-0.80 (m, 4H), 0.65-0.58 (m, 2H); MS (ES+) m/z 442.1 (M+1).

Example 2 Synthesis of(R)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, and making variationas required to replace (S)-tert-butyl pyrrolidine-2-carboxylatehydrochloride with (R)-tert-butyl pyrrolidine-2-carboxylatehydrochloride, the title compound was obtained as an colorless solid(0.26 g, 58% in 2 steps): ¹H NMR (300 MHz, CDCl₃) δ6.95 (d, J=8.1 Hz,1H), 6.51 (d, J=12.0 Hz, 1H), 4.75-4.69 (m, 1H), 3.55-3.37 (m, 4H),2.55-2.40 (m, 1H), 2.19-1.64 (m, 17H), 0.96-0.80 (m, 4H), 0.65-0.58 (m,2H); MS (ES+) m/z 442.1 (M+1).

Example 3 Synthesisof(S)-1-(5-cyclopropyl-2-fluoro-4-((3,5,7-trimethyladamantan-1-yl)methoxy)benzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of(S)-tert-butyl1-(5-cyclopropyl-2-fluoro-4-((3,5,7-trimethyladamantan-1-yl)methoxy)benzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-2-fluoro-4-((3,5,7-trimethyladamantan-1-yl)methoxy)benzoicacid, the title compound was obtained as an colorless foam (0.49 g,90%): ¹H NMR (300 MHz, CDCl₃) δ 6.90 (d, J=7.8 Hz, 1H), 6.44 (d, J=11.7Hz, 1H), 4.46-4.40 (m, 1H), 3.72-3.30 (m, 4H), 2.29-2.15 (m, 1H),2.01-1.75 (m, 4H), 1.43 (s, 6H), 1.23 (s, 3H), 1.19 (s, 6H), 1.05 (s,6H), 0.86-0.77 (m, 11H), 0.59-0.50 (m, 2H),

Step 2. Preparationof(S)-1-(5-cyclopropyl-2-fluoro-4-((3,5,7-trimethyladamantan-1-yl)methoxy)benzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(5-cyclopropyl-2-fluoro-4-((3,5,7-trimethyladamantan-1-yl)methoxy)benzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as an colorless solid (0.40 g, 82%): ¹HNMR (300 MHz, CDCl₃) δ 6.95 (d, J=7.8 Hz, 1H), 6.50 (d, J=12.0 Hz, 1H),4.75-4.69 (m, 1H), 3.58-3.36 (m, 4H), 2.55-2.41 (m, 1H), 2.21-1.80 (m,4H), 1.23 (s, 6H), 1.09 (s, 6H), 0.94-0.80 (m, 11H), 0.65-0.58 (m, 2H);MS (ES+) m/z 484.2 (M+1).

Example 4 Synthesisof(S)-1-(5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoicacid, the title compound was obtained as an colorless foam (0.26 g,47%): ¹H NMR (300 MHz, CDCl₃) δ 6.96 (d, J=7.8 Hz, 1H), 6.46 (d, J=11.1Hz, 1H), 4.48-4.41 (m, 1H), 3.78-3.69 (m, 2H), 3.56-3.43 (m, 1H),3.39-3.30 (m, 1H), 2.30-1.88 (m, 11H), 1.80 (s, 6H), 1.44 (s, 9H),0.90-0.78 (m, 2H), 0.59-0.52 (m, 2H),

Step 2.(S)-1-(5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoyl)-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(5-cyclopropyl-2-fluoro-4-((3,5,7-trifluoroadamantan-1-yl)methoxy)benzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as an colorless solid (0.21 g, 90%): ¹HNMR (300 MHz, CDCl₃) δ 7.00 (d, J=7.8 Hz, 1H), 6.50 (d, J=11.4 Hz, 1H),4.73-4.65 (m, 1H), 3.79 (s, 2H), 3.54-3.38 (m, 2H), 2.44-1.69 (m, 17H),0.95-0.80 (m, 2H), 0.65-0.57 (m, 2H); MS (ES+) m/z 496.1 (M+1).

Example 5 Synthesisof(S)-1-(5-cyclopropyl-4-(((R)-2-(3,5-dichlorobenzyl)morpholino)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Step 1. Preparation of (R)-1-chloro-3-(3,5-dichlorophenyl)propan-2-ol

A 250 mL flask was charged with magnesium turnings (1.90 g, 78.00 mmol)and heated via heat gun under hi-vac. The flask was cooled to ambienttemperature and flushed with argon before freshly distilled diethylether (9 mL) and 1,2-dibromoethane (2 drops) were added. The flask wasequipped with a condenser before a solution of1-bromo-3,5-dichlorobenzene (17.64 g, 78.00 mmol) in diethyl ether (84mL) was added dropwise so as to maintain a gentle reflux. The cloudysolution was stirred for 1 hour at ambient temperature. After cooling to0° C., copper iodide (1.49 g, 7.80 mmol) was added. After 10 minutesstirring, a solution of (R)-epichlorohydrin (5.1 mL, 65.00 mmol) indiethyl ether (84 mL) was added dropwise. The resulting solution wasslowly warmed to ambient temperature and stirred for 18 hours. Thereaction mixture was cooled to 0° C., quenched with saturated aqueousammonium chloride solution (60 mL), and then poured into water (250 mL).The biphasic mixture was stirred until all solids dissolved. The organiclayer was separated and the aqueous layer was extracted with ethylacetate (3×100 mL). The combined organics were washed with brine (150mL); dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified using flash chromatography (0% to 10% ethyl acetatein hexanes) to yield the title compound as a colorless oil (12.93 g,69%): ¹H NMR (300 MHz, CDCl₃) δ 7.27-7.24 (m, 1H), 7.18-7.12 (m, 2H),4.09-3.98 (m, 1H), 3.62 (dd, J=3.9, 11.2 Hz 1H), 3.49 (dd, J=6.3, 11.2Hz, 1H), 2.87-2.79 (m, 2H), 2.22 (br s, 1H),

Step 2. Preparation of (R)-2-(3,5-dichlorobenzyl)morpholine

To a solution of sodium hydroxide (12.96 g, 324.0 mmol) in water (26 mL)was added a solution of (R)-1-chloro-3-(3,5-dichlorophenyl)propan-2-ol(12.93 g, 54.0 mmol) in methanol (56 mL). After 5 min, 2-aminoethylhydrogen sulfate (30.49 g, 215.6 mmol) was added in six portions. Theresulting suspension was heated at 40° C. for 3.5 hours. Toluene (130mL) and sodium hydroxide (12.96 g, 324.0 mmol) were added. The reactionmixture was stirred at 65° C. for 18 hours. After cooling to ambienttemperature, the toluene layer was isolated and washed with water (200mL). The combined aqueous layers were diluted with water (200 mL) andextracted with toluene (200 mL×2). The combined organics were washedwith water (150 mL) and brine (100 mL); dried over sodium sulfate, andconcentrated. The residue was purified using flash chromatography [0% to100% (85:14:1 dichloromethane/ethanol/ammonium hydroxide) indichloromethane] to yield the title compound as a colorless oil (6.98 g,53%); MS (ES+) m/z 246.1, 248.1 (M+1).

Step 3. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-(iodomethyl)benzoate

To a suspension of polymer bound triphenylphosphine (2.60 g, 7.80 mmol)in dichloromethane (60 mL) was added imidazole (0.53 g, 7.80 mmol)followed by iodine (2.00 g, 7.80 mmol). After 5 minutes, tert-butyl5-cyclopropyl-2-fluoro-4-(hydroxymethyl)benzoate (1.60 g, 6.00 mmol) wasadded. Stirring was continued at ambient temperature for 18 hours, thereaction mixture was filtered and the filtrate was washed with saturatedaqueous sodium bisulfate solution (50 mL), and water (50 mL). Theorganic layer was dried over sodium sulfate, and concentrated. Theresidue was dissolved in ethyl acetate (100 mL) and washed withsaturated aqueous sodium bisulfate solution (20 mL), 1.0 N hydrochloricacid solution (20 mL), and brine (20 mL). The organic layer was driedover sodium sulfate, and concentrated to yield the title compound as ayellow solid (2.14 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ7.50 (d, J=7.3 Hz,1H), 7.05 (d, J=10.9 Hz, 1H), 4.58 (m, 2H), 1.97-1.84 (m, 1H), 1.58 (s,9H), 1.08-0.99 (m, 2H), 0.78-0.70 (m, 2H),

Step 4. Preparation of (R)-tert-butyl5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)-methyl)-2-fluorobenzoate

To a microwave vial was added tert-butyl5-cyclopropyl-2-fluoro-4-(iodomethyl)benzoate (0.14 g, 0.37 mmol),(R)-2-(3,5-dichlorobenzyl)morpholine (0.18 g, 0.75 mmol), potassiumphosphate (0.16 g, 0.75 mmol) and N,N-dimethyl formamide (8 mL). Thereaction mixture was heated in the microwave reactor at 80° C. for 2hours, cooled to ambient temperature and diluted with water (200 mL) andethyl acetate (100 mL). The organic layer was separated and the aqueouslayer was extracted with ethyl acetate (50 mL×3). The combined organicswere concentrated and the residue was purified by flash chromatography(0% to 10% ethyl acetate in hexanes) to yield the title compound (0.18g, 98%); MS (ES+) m/z 494.2, 496.2 (M+1).

Step 5. Preparation of(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)methyl)-2-fluorobenzoicacid hydrochloride

A solution of (R)-tert-butyl5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)-methyl)-2-fluorobenzoate(0.18 g, 0.36 mmol) and concentrated hydrochloric acid (0.8 mL, 9.46mmol) in 1,4-dioxane (4 mL) was stirred at ambient temperature for 18hours. The reaction mixture was diluted with toluene (10 mL) andconcentrated in vacuo. The residue was dried to yield the title compoundas a white solid (0.08 g, 49%); MS (ES+) m/z 437.9, 439.9 (M+1); MS(ES−) m/z 436.0, 438.0 (M−1).

Step 6. Preparation of (S)-tert-butyl1-(5-cyclopropyl-4-(((R)-2-(3,5-dichlorobenzyl)morpholino)-methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with(R)-5-cyclopropyl-4-((2-(3,5-dichlorobenzyl)morpholino)methyl)-2-fluorobenzoicacid hydrochloride, the title compound was obtained as a white solid(0.09 g, 80%); MS (ES+) m/z 591.2, 593.2 (M+1).

Step 7. Preparation of(S)-1-(5-cyclopropyl-4-(((R)-2-(3,5-dichlorobenzyl)morpholino)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

To a solution of (S)-tert-butyl1-(5-cyclopropyl-4-(((R)-2-(3,5-dichlorobenzyl)morpholino)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylate (0.09 g, 0.15 mmol) indichloromethane (2 mL) was added trifluoroacetic acid (2 mL). Thereaction mixture was stirred at ambient temperature for 18 hours, andconcentrated in vacuo. The residue was dissolved in ethyl acetate (20mL) and washed with saturated ammonium chloride solution (10 mL×2). Theorganic layer was dried over anhydrous sodium sulfate and concentratedin vacuo. The residue was purified by reverse-phase preparative HPLC toyield the title compound as a colorless solid (0.06 g, 69%): ¹H NMR (300MHz. DMSO-d₆) δ 7.49-7.38 (m, 2H), 7.30 (d, J=1.8 Hz, 2H) 6.99 (d, J=6.8Hz, 0.7H), 6.90 (d, J=6.8 Hz, 0.3H), 4.58-4.52 (m, 2H), 4.37 (dd, J=4.3,8.7 Hz, 1H), 4.12-3.94 (m, 2H), 3.94-3.80 (m 1H), 3.77-3.60 (m, 1H),3.39-3.08 (m, 4H), 3.03-2.69 (m, 3H), 2.34-2.18 (m, 1H), 2.18-2.05 (m,1H), 2.00-1.74 (m, 3H), 1.07-0.92 (m, 2H), 0.78-0.56 (m, 2H); MS (ES+)m/z 535.1, 537.1 (M+1), (ES−) m/z 533.2, 535.2 (M−1).

Example 6 Synthesis of1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-cyclopropanecarboxylicacid

Step 1. Preparation of ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-cyclopropanecarboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with ethyl1-aminocyclopropanecarboxylate hydrochloride, the title compound wasobtained as an colorless foam (0.88 g, 96%): ¹H NMR (300 MHz, CDCl₃) δ7.59 (d, J=9.3 Hz, 1H), 7.08 (d, J=14.1 Hz, 1H), 6.48 (d, J=14.4 Hz,1H), 4.12 (q, J=7.2 Hz, 2H), 3.50 (s, 2H), 2.11-1.97 (m, 4H), 1.79-1.58(m, 14H), 1.25-1.16 (m, 5H), 0.92-0.84 (m, 2H), 0.68-0.62 (m, 2H),

Step 2. Preparation of1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropanecarboxylicacid

To a solution of ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropanecarboxylate(0.23 g, 0.50 mmol) in tetrahydrofuran (20 mL) and water (4 mL) wasadded lithium hydroxide (0.06 g, 2.50 mmol). The reaction mixture wasstirred at ambient temperature for 50 hours, and then concentrated invacuo to remove most of volatiles. The residue was acidified to pH˜1with 5% hydrochloric acid solution: the solid was collected byfiltration and washed with hexanes to give the title compound as acolorless solid (0.20 g, 93%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.44 (d,J=5.4 Hz, 1H), 7.16 (d, J=8.7 Hz, 1H), 6.84 (d, J=13.2 Hz, 1H), 3.61 (s,2H), 2.02-1.93 (m, 4H), 1.76-1.62 (m, 12H), 1.28-1.13 (m, 5H), 0.94-0.86(m, 2H), 0.63-0.57 (m, 2H); MS(ES+) m/z 428.2 (M+1).

Example 7 Synthesis of1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-methylbenzamido)-cyclopropanecarboxylicacid

Step 1. Preparation of ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-methylbenzamido)cyclopropanecarboxylate

To a solution of ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-cyclopropanecarboxylate(0.28 g, 0.61 mmol) in N,N-dimethyl formamide (20 mL) was added cesiumcarbonate (0.80 g, 2.45 mmol) and iodomethane (0.15 mL, 2.40 mmol). Thereaction mixture was stirred at ambient for 50 hours, diluted with ethylacetate (200 mL), and washed with water and brine; dried over anhydroussodium sulfate and concentrated in vacuo. Purification of the residue bycolumn chromatography (10/o ethyl acetate in hexanes) afforded the titlecompound as a colorless solid (0.24 g, 83%): ¹H NMR (300 MHz, CDCl₃)δ6.91 (d, J=7.8 Hz, 0.5H), 6.73 (d, J=7.8 Hz, 0.5H), 6.50-6.42 (m, 1H),4.22-4.04 (m, 2H), 3.46 (s, 2H), 3.11 (s, 1.5H), 2.92 (s, 1.5H),2.08-1.94 (m, 4H), 1.82-1.55 (m, 13H), 1.32-1.18 (m, 5H), 1.10-0.95 (m,1H), 0.90-0.79 (m, 2H), 0.63-0.44 (m, 2H),

Step 2. Preparation of1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-methylbenzamido)cyclopropanecarboxylicacid

To a solution of ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-methylbenzamido)cyclopropanecarboxylate(0.24 g, 0.51 mmol) in tetrahydrofuran (20 mL) and water (4 mL) wasadded lithium hydroxide (0.10 g, 4.16 mmol). The reaction mixture washeated at 70° C. for 20 hours, and then concentrated in vacuo to removemost of volatiles. The residue was acidified to pH˜1 with 10%hydrochloric acid solution; the solid was collected by filtration andwashed with hexanes to give the title compound as a colorless solid(0.21 g, 93%): ¹H NMR (300 MHz, CDCl₃) δ 11.65 (br s, 1H), 6.99 (d,J=7.8 Hz, 0.6H), 6.81 (d, J=7.8 Hz, 0.4H), 6.53-6.42 (m, 1H), 3.47 (s,2H), 3.13 (s, 1H), 2.96 (s, 2H), 2.01 (br s, 4H), 1.79-1.62 (m, 12H),1.42-1.08 (m, 4H), 0.91-0.82 (m, 2H), 0.65-0.43 (m, 2H); MS (ES+) m/z442.1 (M+1).

Example 8 Synthesis of2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-2-methylpropanoicacid

Step 1. Preparation of methyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-2-methylpropanoate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with methyl2-amino-2-methylpropanoate hydrochloride, the title compound wasobtained as an colorless foam (0.34 g, 76%): ¹H NMR (300 MHz, CDCl₃) δ7.53 (d, J=9.3 Hz, 1H), 7.15 (d, J=14.7 Hz, 1H), 6.47 (d, J=14.1 Hz,1H), 3.71 (s, 3H), 3.48 (s, 2H), 2.03 (br s, 4H), 1.76-1.58 (m, 18H),0.88-0.80 (m, 2H), 0.66-0.59 (m, 2H),

Step 2. Preparation of2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-2-methylpropanoicacid

Following the procedure as described in Example 6 step 2, and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-cyclopropanecarboxylatewith methyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-2-methylpropanoate,the title compound was obtained as an colorless foam (0.23 g, 98%): ¹HNMR (300 MHz, CDCl₃) δ 7.55 (d, J=9.3 Hz, 1H), 7.13 (d, J=15.3 Hz, 1H),6.48 (d, J=15.6 Hz, 1H), 3.50 (s, 2H), 2.01 (br s, 4H), 1.78-1.59 (m,18H), 0.92-0.84 (m, 2H), 0.68-0.61 (m, 2H); MS (ES+) m/z 430.1 (M+1).

Example 9 Synthesis of(R)-1-(5-cyclopropyl-4-(1-(3,4-dichlorophenoxy)ethyl)-2-fluorobenzamido)cyclopropanecarboxylicacid

Step 1. Preparation of (R)-ethyl1-(5-cyclopropyl-4-(1-(3,4-dichlorophenoxy)ethyl)-2-fluorobenzamido)cyclopropanecarboxylate

Following the procedure as described in Example 1 step 1, and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with(R)-5-cyclopropyl-4-(1-(3,4-dichlorophenoxy)ethyl)-2-fluorobenzoic acidand to replace (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloridewith ethyl 1-aminocyclopropanecarboxylate hydrochloride, the titlecompound was obtained as an colorless foam (0.17 g, 70%): ¹H NMR (300MHz, CDCl₃) δ 772 (d, J=7.5 Hz, 1H), 7.21-7.06 (m, 3H), 6.86-6.83 (m,1H), 6.63-6.55 (m, 1H), 5.69 (q, J=6.9 Hz, 1H), 4.10 (q, J=9.0 Hz, 2H),1.90-1.79 (m, 1H), 1.65-1.58 (m, 5H), 1.26-1.14 (m, 5H), 1.10-0.93 (m,2H), 0.90-0.82 (m, 1H), 0.77-0.68 (m, 1H),

Step 2. Preparation of(R)-1-(5-cyclopropyl-4-(1-(3,4-dichlorophenoxy)ethyl)-2-fluorobenzamido)cyclopropanecarboxylicacid

Following the procedure as described in Example 6 step 2, and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-cyclopropanecarboxylatewith (R)-ethyl1-(5-cyclopropyl-4-(1-(3,4-dichlorophenoxy)ethyl)-2-fluorobenzamido)cyclopropanecarboxylate,the title compound was obtained as an colorless solid (0.11 g, 69%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.45 (br s, 1H), 8.69 (s, 1H), 744 (d, J=8.7Hz, 1H), 7.17-7.09 (m, 3H), 6.89-6.83 (m, 1H), 5.93 (q, J=12.3 Hz, 1H),2.14-2.03 (m, 1H), 1.55 (d, J=6.3 Hz, 3H), 1.33-1.27 (m, 2H), 1.17-0.90(m, 4H), 0.78-0.61 (m, 2H); MS(ES−) m/z 450.0, 452.0 (M−1).

Example 10 Synthesis of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-methoxypropanoicacid

Step 1. Preparation of (S)-methyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-methoxypropanoate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with (S)-methyl2-amino-3-methoxypropanoate hydrochloride (0.04 g, 0.24 mmol) (preparedas described in Tetrahedron: Asymmetry 1998, 9, 3841), the titlecompound was obtained as an colorless solid (0.08 g, 87%): MS (ES+) m/z460.2 (M+1).

Step 2. Preparation of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-methoxypropanoicacid

To a solution of(S)-methyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-methoxypropanoate(0.08 g, 0.17 mmol) in tetrahydrofuran (1.8 mL) was added 0.2M lithiumhydroxide solution (0.88 mL, 0.17 mmol). After stirring at ambienttemperature for 1 hour, the reaction mixture was diluted with diethylether (20 mL). The aqueous layer was isolated and extracted with diethylether (20 mL×2). The aqueous layer was acidified to pH˜1 with 5% aqueoushydrochloric acid solution and extracted with ethyl acetate (50 mL×3).The combined organic extracts were dried over anhydrous sodium sulfate,and concentrated. The residue was purified by flash chromatography [0%to 40% ethyl acetate in hexanes (with 0.10% formic acid as additive)] toyield the title compound as a colorless solid (0.05 g, 67%): ¹H NMR (300MHz. CDCl₃) δ 7.59 (d, J=9.1 Hz, 2H) 7.49 (dd, J=7.1, 13.8 Hz, 1H), 6.52(d, J=14.1 Hz, 1H), 4.93-4.88 (m, 1H), 3.97 (dd, J=3.4, 9.6 Hz, 1H),3.75 (dd, J=3.7, 9.6 Hz, 1H), 3.53 (s, 2H), 3.41 (s, 3H), 2.09-1.98 (m,4H), 1.82-1.64 (m, 12H), 0.96-0.85 (m, 2H), 0.71-0.64 (m, 2H); MS (ES+)m/z 446.2 (M+1), (ES−) m/z 444.3 (M−1).

Example 11 Synthesis of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)propanoicacid

Step 1. Preparation of (S)-methyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)propanoate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with (S)-methyl2-aminopropanoate hydrochloride, the title compound was obtained as ancolorless foam (0.70 g, 81%): ¹H NMR (300 MHz, CDCl₃) δ 7.57 (d, J=9.0Hz, 1H), 7.22-7.14 (m, 1H), 6.50 (d, J=14.1 Hz, 1H), 4.82-4.70 (m, 1H),3.76 (s, 3H), 3.51 (s, 2H), 2.08-1.98 (m, 4H), 1.80-1.64 (m, 12H), 1.48(d, J=7.2 Hz, 3H), 0.93-0.85 (m, 2H), 0.68-0.62 (m, 2H),

Step 2. Preparation of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)propanoicacid

To a solution of (S)-methyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)propanoate(0.35 g, 0.81 mmol) in tetrahydrofuran (20 mL) and water (4 mL) wasadded lithium hydroxide (0.03 g, 1.25 mmol). The reaction mixture wasstirred at ambient for 20 hours, and then concentrated in vacuo toremove most of volatiles. The residue was acidified to pH˜1 with 5%hydrochloric acid aqueous solution; the solid was collected byfiltration and washed with hexanes to give the title compound as acolorless solid (0.28 g, 83%): ¹H NMR (300 MHz, CDCl₃) δ7.56 (d, J=9.0Hz, 1H), 7.19-7.11 (m, 1H), 6.50 (d, J=14.4 Hz, 1H), 4.78-4.69 (m 1H),3.51 (s, 2H), 2.02 (br s, 4H), 1.79-1.64 (m 12H), 1.54 (d, J=7.2 Hz,3H), 0.93-0.85 (m, 2H), 0.68-0.62 (m, 2H); MS (ES+) m/z 416.1 (M+1).

Example 12 Synthesis of(S)-1-(5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of(S)-tert-butyl1-(5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless oil (0.47 g, 93%):¹H NMR (300 MHz, CDCl₃) δ 7.04-6.88 (m, 1H), 6.57-6.43 (m, 1H),4.54-4.18 (m, 1H), 3.82-3.34 (m, 4H), 2.36-2.19 (m, 1H), 2.08-1.72 (m,10H), 1.67-1.60 (m, 2H), 1.54-1.11 (m, 12H), 0.92-0.81 (m, 2H),0.65-0.54 (m, 2H); MS (ES+) m/z 496.3 (M+1).

Step 2. Preparation of(S)-1-(5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(5-cyclopropyl-4-((4,4-difluoro-1-methylcyclohexyl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.22 g, 54%): ¹HNMR (300 MHz, CDCl₃) δ7.05-6.97 (m, 1H), 6.59-6.50 (m, 1H), 4.80-4.69(m, 1H), 3.71 (s, 2H), 3.57-3.38 (m, 2H), 2.56-2.41 (m, 1H), 2.26-2.09(m, 1H), 2.07-1.74 (m, 9H), 1.67-1.55 (m, 2H), 1.16 (s, 3H), 0.96-0.86(m, 2H), 0.67-0.57 (m, 2H); MS (ES+) m/z 440.2 (M+1).

Example 13 Synthesis of(S)-1-(4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid, the titlecompound was obtained as a colorless oil (0.36 g, 79%): ¹H NMR (300 MHz,CDCl₃) δ 6.96-6.82 (m, 1H), 6.56-6.44 (m, 1H), 4.54-4.19 (m, 1H),3.83-3.34 (m, 4H), 2.35-2.18 (m, 1H), 2.11-1.65 (m, 10H), 1.53-0.99 (m,14H), 0.93-0.79 (m, 2H), 0.67-0.52 (m, 2H); MS (ES+) m/z 446.2 (M+1).

Step 2. Preparationof(S)-1-(4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.20 g, 65%): ¹HNMR (300 MHz, CDCl₃) δ 6.98-6.91 (m, 1H), 6.58-6.49 (m, 1H), 4.77-4.70(m, 1H), 3.82-3.73 (m, 2H), 3.59-3.37 (m, 2H), 2.57-2.43 (m, 1H),2.25-1.67 (m, 10H), 1.41-1.04 (m, 5H), 0.98-0.81 (m, 2H), 0.71-0.55 (m,2H); MS (ES−) m/z 388.2 (M−1).

Example 14 Synthesisof(S)-1-(5-cyclopropyl-4-((R)-1-(3,4-dichlorophenoxy)ethyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(5-cyclopropyl-4-((R)-1-(3,4-dichlorophenoxy)ethyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with(R)-5-cyclopropyl-4-(1-(3,4-dichlorophenoxy)ethyl)-2-fluorobenzoic acid,the title compound was obtained as a colorless oil (0.29 g, 91%); MS(ES+) m/z 522.1, 524.1 (M+1).

Step 2. Preparation of(S)-1-(5-cyclopropyl-4-((R)-1-(3,4-dichlorophenoxy)ethyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(5-cyclopropyl-4-((R)-1-(3,4-dichlorophenoxy)ethyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.08 g, 30%): ¹HNMR (300 MHz, CDCl₃) δ 7.26-7.21 (m, 1H), 7.18-7.10 (m, 2H), 6.93-6.87(m, 1H), 6.67-6.56 (m, 1H), 5.81-5.66 (m, 1H), 4.81-4.68 (m, 1H),3.55-3.35 (m, 2H), 2.52-2.37 (m, 1H), 2.30-1.80 (m, 4H), 1.67-1.58 (m,3H), 1.15-0.97 (m, 2H), 0.92-0.67 (m, 2H); MS (ES−) m/z 464.0, 466.0(M−1).

Example 15 Synthesisof(S)-1-(4-((R)-1-((5-chloro-6-cyclopropylpyridin-3-yl)oxy)ethyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(4-((R)-1-((5-chloro-6-cyclopropylpyridin-3-yl)oxy)ethyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with(R)-4-(1-((5-chloro-6-cyclopropylpyridin-3-yl)oxy)ethyl)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a colorless oil (0.42 g, 85%);MS (ES+) m/z 529.2, 531.2 (M+1).

Step 2. Preparation of(S)-1-(4-((R)-1-((5-chloro-6-cyclopropylpyridin-3-yl)oxy)ethyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-((R)-1-((5-chloro-6-cyclopropylpyridin-3-yl)oxy)ethyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.10 g, 27%): ¹HNMR (300 MHz, CDCl₃) δ 7.95-7.89 (m, 1H), 7.23-7.00 (m, 3H), 5.80-5.64(m, 1H), 4.79-4.54 (m, 1H), 3.49-3.20 (m, 2H), 2.42-2.26 (m, 2H),2.13-1.92 (m, 2H), 1.89-1.56 (m, 5H), 1.06-0.62 (m, 8H), MS(ES+) m/z:473.2, 475.1 (M+1).

Example 16 Synthesis of(2S)-1-(5-cyclopropyl-4-((3,3-dimethylcyclohexyl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (2S)-tert-butyl1-(5-cyclopropyl-4-((3,3-dimethylcyclohexyl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((3,3-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid,the title compound was obtained as a colorless oil (0.33 g, 97%); MS(ES+) m/z 474.3 (M+1).

Step 2. Preparation of(2S)-1-(5-cyclopropyl-4-((3,3-dimethylcyclohexyl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (2S)-tert-butyl1-(5-cyclopropyl-4-((3,3-dimethylcyclohexyl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.23 g, 79%): ¹HNMR (300 MHz, CDCl₃) δ 6.97-6.92 (m, 1H), 6.57-6.49 (m, 1H), 4.78-4.70(m, 1H), 3.81-3.68 (m, 2H), 3.58-3.38 (m, 2H), 2.57-2.44 (m, 1H),2.24-1.83 (m, 6H), 1.70-1.35 (m, 4H), 1.20-1.05 (m 1H), 1.05-0.84 (m,10H), 0.68-0.56 (m 2H); MS (ES+) m/z 418.1 (M+1).

Example 17 Synthesis of(S)-1-(4-(adamantan-1-ylmethoxy)-2-fluoro-5-isopropylbenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of(S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-2-fluoro-5-isopropylbenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-2-fluoro-5-isopropylbenzoic acid, the titlecompound was obtained as a colorless oil (0.31 g, 86%); MS (ES+) m/z500.3 (M+1).

Step 2. Preparation of(S)-1-(4-(adamantan-1-ylmethoxy)-2-fluoro-5-isopropylbenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-2-fluoro-5-isopropylbenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.22 g, 79%): ¹HNMR (300 MHz, CDCl₃) δ 7.29-7.22 (m, 1H), 6.59-6.50 (m, 1H), 4.81-4.71(m, 1H), 3.63-3.38 (m, 4H), 3.34-3.18 (m, 1H), 2.62-2.48 (m, 1H),2.25-1.58 (m, 18H), 1.27-1.13 (m, 6H); MS (ES+) m/z 444.1 (M+1).

Example 18 Synthesisof(S)-1-(5-cyclopropyl-2-fluoro-4-(((1R,2s,3S,5R,7R)-5-fluoroadamantan-2-yl)oxy)benzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(5-cyclopropyl-2-fluoro-4-(((1R,2s,3S,5R,7R)-5-fluoroadamantan-2-yl)oxy)benzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-2-fluoro-4-(((1R,2s,3S,5s,7s)-5-fluoroadamantan-2-yl)oxy)benzoicacid, the title compound was obtained as a colorless oil (0.33 g, 91%);MS(ES+) m/z 502.2 (M+1).

Step 2. Preparationof(S)-1-(5-cyclopropyl-2-fluoro-4-(((1R,2s,3S,5R,7R)-5-fluoroadamantan-2-yl)oxy)benzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith S)-tert-butyl1-(5-cyclopropyl-2-fluoro-4-(((1R,2s,3S,5R,7R)-5-fluoroadamantan-2-yl)oxy)benzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.13 g, 44%): ¹HNMR (300 MHz, CDCl₃) δ 7.02-6.96 (m, 1H), 6.56-6.48 (m, 1H), 4.80-4.70(m, 1H), 4.47-4.43 (m, 1H), 3.60-3.38 (m, 2H), 2.58-2.39 (m, 3H),2.36-1.83 (m, 13H), 1.54-1.42 (m, 2H), 0.97-0.85 (m, 2H), 0.70-0.59 (m,2H); MS(ES+) m/z 446.0 (M+1).

Example 19 Synthesisof(S)-1-(4-(((1R,3S,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Step 1. Preparation of (S)-tert-butyl1-(4-(((1R,3S,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

A mixture of4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]-octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoicacid hydrochloride (0.21 g, 0.39 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.11 g,0.57 mmol), 4-dimethylaminopyridine (0.19 g, 1.52 mmol), and(S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride (0.12 g, 0.57mmol) in dichloromethane (10 mL) was stirred at ambient temperature for16 hours. The reaction mixture was diluted with ethyl acetate (50 mL),washed with 1.0 M hydrochloric acid (20 mL), brine (20 mL), dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by flash chromatography (2:1 of hexanes:ethylacetate) to provide the title compound as an oil (0.21 g, 81%): ¹H NMR(300 MHz, CDCl₃) δ 7.29 (d, J=11.0 Hz, 1H), 7.05 (d, J=6.8 Hz, 1H), 6.76(d, J=12.7 Hz, 2H), 6.55 (s, 1H), 4.53-4.46 (m, 2H), 3.82-3.70 (m, 1H),3.67-3.60 (m, 2H), 3.56-3.45 (m, 1H), 3.43-3.32 (m, 1H), 3.19-3.11 (m,2H), 2.34-2.21 (m, 1H), 2.20-2.09 (m, 2H), 2.05-2.00 (m, 3H), 2.00-1.78(m, 6H), 1.47 (s, 9H), 0.90-0.80 (m, 2H), 0.62-0.52 (m, 2H) (Note: 2rotamers observed. Data given for dominant rotamer.); MS (ES+) m/z667.2, 669.2 (M+1).

Step 2. Preparation of(S)-1-(4-(((1R,3S,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

A solution of (S)-tert-butyl1-(4-(((1R,3S,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate(0.21 g, 0.31 mmol) in dichloromethane (30 mL) was treated withtrifluoroacetic acid (10 mL).

The resulting mixture was stirred at ambient temperature for 16 h andthen concentrated in vacuo to provide the title compound as a colorlesssolid (0.22 g, quant. yield): 1H NMR (300 MHz, DMSO-d₆) δ 12.62 (br s,1H), 9.65 (br s, 1H), 7.55 (d, J=10.3 Hz, 1H), 7.22-7.18 (m, 1H),7.11-7.03 (m, 2H), 7.01 (d, J=6.8 Hz, 1H), 4.83-4.73 (m, 1H), 4.45-4.30(m, 2H), 4.12-3.90 (m, 3H), 3.35-3.18 (m, 2H), 2.36-2.18 (m, 5H),2.15-2.03 (m, 2H), 1.96-1.74 (m/z 3H), 1.29-1.15 (m, 2H), 1.03-0.92 (m,2H), 0.87-0.78 (m, 1H), 0.74-0.65 (m, 2H) (Note: 2 rotamers observed.Data given for dominant rotamer.); MS (ES+) m/z 611.2, 613.3 (M+1).

Example 20 Synthesis of(S)-1-(4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Step 1. Preparation of (S)-tert-butyl1-(4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)-piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 19 step 1, and makingvariation as required to replace4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoicacid hydrochloride with4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoicacid hydrochloride, the title compound was obtained as an oil (0.39 g,97%): ¹H NMR (300 MHz, CDCl₃) δ 7.14 (d, J=10.7 Hz, 1H), 7.06 (d, J=6.7Hz, 1H), 6.83-6.76 (m, 2H), 6.65-6.61 (m, 1H), 4.49 (dd, J=8.4, 4.8 Hz,1H), 4.36-4.25 (m, 1H), 3.80-3.70 (m, 1H), 3.65-3.59 (m, 2H), 3.41-3.32(m, 1H), 2.75-2.65 (m, 2H), 2.40-2.20 (m, 3H), 2.04-1.90 (m, 5H),1.86-1.74 (m, 3H), 1.47 (s, 9H), 0.92-0.82 (m, 2H), 0.63-0.54 (m, 2H)(Note: 2 rotamers observed. Data given for dominant rotamer.); MS (ES+)m/z 641.2, 643.2 (M+1).

Step 2.(S)-1-(4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Following the procedure as described in Example 19, step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(((1R,3S,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-((4-(3-chloro-5-(trifluoromethoxy)phenoxy)piperidin-1-yl)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.28 g, 66%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.53 (br s, 1H), 9.83 (br s, 1H), 7.49 (d,J=10.3 Hz, 1H), 7.25-7.16 (m 1H), 7.13-6.84 (m, 3H), 4.91-4.80 (m, 1H),4.53 (s, 2H), 4.34 (dd, J=8.3, 4.1 Hz, 1H), 3.59-3.43 (m, 2H), 3.39-3.13(m, 3H), 2.31-1.98 (m, 4H), 1.96-1.71 (m, 4H), 1.34-1.15 (m, 1H),1.05-0.92 (m, 2H), 0.87-0.77 (m, 1H), 0.73-0.059 (m, 2H) (Note: 2rotamers observed. Data given for dominant rotamer.); MS (ES+) m/z585.2, 587.2 (M+1).

Example 21 Synthesis of(S)-1-(4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Step 1. Preparation of (S)-tert-butyl1-(4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 19 step 1, and makingvariation as required to replace4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoicacid hydrochloride with4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as an oil (0.46 g, 94%): ¹H NMR(300 MHz, CDCl₃) δ 8.16 (s, 1H), 6.93 (d, J=7.7 Hz, 1H), 6.52 (d, J=11.4Hz, 1H), 6.46 (s, 1H), 4.46 (dd, J=8.4, 5.0 Hz, 1H), 4.20-4.05 (m, 2H),4.00-3.91 (m, 2H), 3.88-3.69 (m, 2H), 3.54-3.43 (m, 1H), 3.40-3.30 (m,1H), 2.32-2.18 (m, 1H), 2.01-1.65 (m, 4H), 1.46 (s, 9H), 1.25 (s, 3H),0.70-0.59 (m, 2H), 0.56-0.45 (m, 2H) (Note: 2 rotamers observed. Datagiven for dominant rotamer.); MS (ES+) m/z 612.1, 614.1 (M+1).

Step 2. Preparationof(S)-1-(4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Following the procedure as described in Example 19 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(((1R,3S,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-((1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylateand purification by HPLC (Gemini NX, 5 μm, 30×150 mm; acetonitrile (plus0.1% trifluoroacetic acid) in water (plus 0.1% trifluoroacetic acid):20% acetonitrile for 2.5 minutes, 20->80% over 25 minutes), the titlecompound was obtained as a colorless solid (0.16 g, 32%): ¹H NMR (300MHz, DMSO-d₆) δ 11.31 (br s, 2H), 8.27 (s, 1H), 6.91 (d, J=11.8 Hz, 1H),6.77-6.72 (m, 2H), 4.29 (dd, J=8.3, 4.1 Hz, 1H), 4.08-3.98 (m, 4H), 3.78(d, J=8.9 Hz, 2H), 3.35-3.19 (m, 2H), 2.27-2.12 (m, 1H), 1.93-1.72 (m,3H), 1.70-1.60 (m, 1H), 1.39 (s, 3H), 0.59-0.42 (m, 4H) (Note: 2rotamers observed. Data given for dominant rotamer.); MS (ES+) m/z556.2, 558.2 (M+1).

Example 22(S)-1-(4-((5-chloro-[1,1′-biphenyl]-2-yl)oxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of methyl4-((5-chloro-[1,1′-biphenyl]-2-yl)oxy)-2,5-difluorobenzoate

To a solution of 5-chloro-[1,1′-biphenyl]-2-ol (5.0 g, 24.4 mmol) inanhydrous dimethyl sulfoxide (50 mL) was added potassium carbonate (5.1g, 36.6 mmol) and methyl 2,4,5-trifluorobenzoate (4.4 g, 24.4 mmol) andthe reaction mixture was stirred at ambient temperature for 16 hours.The reaction mixture was partitioned between ethyl acetate (400 mL) andwater (100 mL), and the organic phase washed with water (50 mL×2), brine(50 mL); dried over anhydrous sodium sulfate and concentrated in vacuoto yield the title compound as a colorless foam (8.9 g, quant. yield):¹H NMR (300 MHz, CDCl₃) δ 7.61 (dd, J=10.9, 6.6 Hz, 1H), 7.48-7.42 (m,3H), 7.37-7.26 (m, 4H), 7.05 (d, J=8.6 Hz, 1H), 6.39 (dd, J=11.1, 6.6Hz, 1H), 3.85 (s, 3H),

Step 2. Preparation of4-((5-chloro-[1,1′-biphenyl]-2-yl-2)oxy)-2,5-difluorobenzoic acid

To a solution of methyl4-((5-chloro-[1,1′-biphenyl]-2-yl)oxy)-2,5-difluorobenzoate (0.5 g, 1.33mmol) in tetrahydrofuran (5 mL) was added a solution of lithiumhydroxide monohydrate (0.28 g, 6.65 mmol) in water (5 mL) and thereaction mixture was stirred at ambient temperature for 16 hours. Thereaction mixture was adjusted to pH˜1-2 with 1 N hydrochloric acid anddiluted with dichloromethane (150 mL). The organic phase was washed withbrine (15 mL), dried over anhydrous sodium sulfate and concentrated invacuo to give the title compound as a colorless solid (0.48 g, quant.yield): MS (ES−) m/z 359.1, 361.1 (M−1).

Step 3. Preparation of (S)-tert-butyl1-(4-((5-chloro-[1,1′-biphenyl]-2-yl)oxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylate

To a solution of4-((5-chloro-[1,1′-biphenyl]-2-yl)oxy)-2,5-difluorobenzoic acid (0.48 g,1.33 mmol) in dichloromethane (10 mL) was addedN-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride (0.77 g,4.00 mmol), 4-(dimethylamino)-pyridine (0.49 mg, 4.00 mmol), and(S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride (0.42 g, 2.00mmol), and the reaction mixture was stirred at ambient temperature for16 hours. After dilution with dichloromethane (10×) mL), the organicphase was washed with 1.0 N hydrochloride solution (2×10 mL), brine (10mL); dried over anhydrous sodium sulfate and concentrated in vacuo togive the title compound as a colorless foam (0.68 g, 99%): MS (ES+) m/z514.1, 516.1 (M+1).

Step 4. Preparation of(S)-1-(4-((5-chloro-[1,1′-biphenyl]-2-yl)oxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylic acid

To a solution of (S)-tert-butyl1-(4-((5-chloro-[1,1′-biphenyl]-2-yl)oxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylate(0.68 g, 1.32 mmol) in dichloromethane (10 mL) was added trifluoroaceticacid (2 mL). The mixture was stirred at ambient temperature for 16hours. After concentration in vacuo, the residue was purified by silicagel chromatography (0 to 100% ethyl acetate in hexanes) to provide thetitle compound as colorless solid (0.30 g, 49%): ¹H NMR (300 MHz, CDCl₃)δ7.50-7.41 (m, 3H), 7.39-7.25 (m, 5H), 7.17 (dd, J=10.0, 6.1 Hz, 1H),7.01 (d, J=8.7 Hz, 1H), 6.45 (dd, J=10.0, 6.4 Hz, 1H), 4.64 (dd, J=7.2,5.5 Hz, 1H), 3.42-3.34 (m, 2H), 2.31-2.20 (m, 2H), 2.07-1.82 (m, 2H); MS(ES−) m/z 456.2, 458.2 (M−1).

Example 23 Synthesisof(S)-1-((4-(adamantan-1-ylmethoxy))-3-chlorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of 4-(adamantan-1-ylmethoxy)-3-chlorobenzoic acid

To a mixture of 1-adamantemethanol (19 g, 115 mmol) in anhydrousdimethyl sulfoxide (700 mL) was added potassium tert-butoxide (32 g, 290mmol) and the reaction mixture was stirred for 10 min at ambienttemperature. 3-chloro-4-fluorobenzoic acid (20 g, 115 mmol) was added tothe reaction mixture, and the resulting thick suspension was allowed tostand at ambient temperature for 16 hours. The reaction mixture waspoured into a mixture of 1 N hydrochloric acid (3(00 mL) and water (300mL) and the precipitated solid was collected by filtration and washedwith water (500 mL), and then dissolved in a mixture of ethyl acetateand tetrahydrofuran (1:1 v/v, 1000 mL). The organic phase was dried overanhydrous magnesium sulfate and concentrated in vacuo to give the titlecompound as a colorless solid (36.7 g, 990%): ¹H NMR (300 MHz, DMSO-d₆)δ 12.90 (br s, 1H), 7.85 (d, J=2.0 Hz, 1H), 7.82 (dd, J=8.5, 2.1 Hz,1H), 7.16 (d, J=8.6 Hz, 1H) 3.64 (s, 2H), 1.98-1.90 (m, 3H), 1.73-1.54(m, 12H),

Step 2. Preparation of (S)-tert-butyl1-((4-(adamantan-1-ylmethoxy))-3-chlorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 22 Step 3 and makingvariation as required to replace4-((5-chloro-[1,1′-biphenyl]-2-yl)oxy)-2,5-difluorobenzoic acid with4-(adamantan-1-ylmethoxy)-3-chlorobenzoic acid, the title compound wasobtained as a colorless solid (0.95 g. quant. yield): MS (ES−) m/z476.3, 478.3 (M+1).

Step 3. Preparation of(S)-1-((4-(adamantan-1-ylmethoxy))-3-chlorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 22 Step 4 and makingvariation as required to replace (S)-tert-butyl1-(4-((5-chloro-[1,1′-biphenyl]-2-yl)oxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy))-3-chlorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.41 g, 48%): ¹HNMR (300 MHz, CDCl₃) δ7.60 (d, J=1.7 Hz, 1H), 7.46 (dd, J=8.5, 1.8 Hz,1H), 6.89 (d, J 8.4 Hz, 1H), 4.76-4.67 (m, 1H), 3.66-3.53 (m, 4H),2.45-2.26 (m, 1H), 2.27-2.13 (m, 1H), 2.10-1.97 (m, 5H), 1.96-1.84 (m,1H), 1.80-1.63 (m, 12H); MS (ES−) m/z 416.2, 418.1 (M−1).

Example 24 Synthesis of(S)-1-(5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Step 1. Preparation of (S)-tert-butyl1-(5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate

To a solution of5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid (0.20 g, 0.50 mmol) in dichloromethane (3 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.17 g, 0.90 mmol),4-dimethylaminopyridine (0.140 g, 1.15 mmol) and (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride (0.09 g, 0.50 mmol). Thereaction mixture was stirred at ambient temperature for 16 hours andconcentrated in vacuo to remove the solvent. The residue was purified bycolumn chromatography eluting with a gradient of 30 to 70% ethyl acetatein hexanes to afford the title compound as an oil (0.20 g, 74%): MS(ES+) m/z 553.1 (M+1).

Step 2. Preparation of(S)-1-(5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

To a solution of(S)-tert-butyl1-(5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate(0.20 g, 0.37 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (3 mL). After stirring at ambient temperature for 4 hours, thereaction mixture was concentrated and purified by preparative HPLC(gradient of acetonitrile in water) to afford the title compound as acolorless solid (0.07 g, 31%): ¹H NMR (300 MHz, DMSO-d₆) δ8.14-7.99 (m,2H), 7.61-7.52 (m, 1H), 7.23-6.88 (m, 1H), 7.17-7.08 (m, 1H), 5.11-4.96(m, 2H), 4.65-3.94 (m, 1H), 4.38-4.17 (m, 1H), 3.58-3.29 (m, 2H),2.32-2.16 (m, 1H), 1.99-1.74 (m, 3H); MS (ES+) m/z 497.0, 499.0 (M+1).

Example 25 Synthesis of(S)-1-(4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid

To a solution of4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoicacid (0.21 g, 0.50 mmol) in dichloromethane (3 mL) was added1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (0.17 g, 0.90 mmol),4-dimethylaminopyridine (0.150 g, 1.25 mmol) and (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride (0.085 g, 0.50 mmol). Thereaction mixture was stirred at ambient temperature for 16 hours andtrifluoroacetic acid (3 mL) was added. After stirring at ambienttemperature for 4 hours, the reaction mixture was concentrated and theresidue was purified by preparative HPLC (gradient of acetonitrile inwater) to afford the title compound as a white solid (0.08 g, 25%): ¹HNMR (300 MHz, DMSO-d₆) δ8.02-7.91 (m, 1H), 7.68-7.61 (m, 1H), 7.56 (d,J=2.62 Hz, 1H), 7.50-7.39 (m, 2H), 7.38-7.26 (m, 1H), 7.24-7.16 (m, 1H),7.15-6.87 (m, 2H), 6.84-6.09 (m, 3H), 4.34-4.14 (m, 1H), 3.56-3.10 (m,2H), 2.29-2.13 (m, 1H), 2.01-1.71 (m, 3H); MS (ES+) m/z 514.1, 516.1(M+1).

Example 26 Synthesis of(2S)-1-(5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Following the procedure as described in Example 25, and making variationas required to replace4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoicacid with5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.03 g,21%): ¹H NMR (300 MHz, CDCl₃) δ7.68-7.55 (m, 4H), 7.51-7.31 (m, 4H),6.92 (d, J=7.7 Hz, 1H), 6.50 (d, J 11.6 Hz, 1H), 4.91-4.77 (br, s, 1H),4.71 (dd, J=7.9, 4.2 Hz, 1H), 3.91-3.82 (m, 2H), 3.68-3.34 (m, 4H),2.80-2.59 (m, 3H), 2.54-2.42 (m, 1H), 2.25-1.82 (m, 9H), 0.92-0.79 (m,2H), 0.62-0.53 (m, 2H); MS (ES+) m/z 627.0, 625.1 (M+1).

Example 27 Synthesisof(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 25, and making variationas required to replace4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoicacid with 4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoic acid,the title compound was obtained as a colorless solid (0.03 g, 31%): ¹HNMR (300 MHz, DMSO-d₆) δ7.08-6.94 (m, 1H), 6.85-6.72 (m, 1H), 4.37-4.09(m, 1H), 3.97-3.81 (br, s, 2H), 3.64-3.25 (m, 5H), 2.32-2.14 (m, 3H),2.13-1.90 (m, 6H), 1.90-1.55 (m, 16H) MS (ES+) m/z 456.1 (M+1).

Example 28 Synthesis of(2S)-1-(5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Following the procedure as described in Example 25, and making variationas required to replace4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoicacid with5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.06 g,44%): ¹H NMR (300 MHz, DMSO-d₆) δ7.64 (t, J=1.7 Hz, 1H), 7.54 (m, 2H),7.49-7.39 (m, 5H), 6.90-6.67 (m, 2H), 5.81-5.72 (br s, 1H), 4.35-4.26(m, 1H), 4.15-4.01 (m, 4H), 3.98-3.88 (m, 2H), 3.54-3.43 (m, 1H),3.33-3.21 (m, 1H), 2.31-2.13 (m, 1H), 2.05-1.70 (m, 5H), 1.43 (s, 3H),0.84-0.73 (m, 2H), 0.57-0.44 (m, 2H); MS (ES+) m/z 613.0, 611.1 (M+1).

Example 29 Synthesis of(S)-1-(4-((1-((3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Following the procedure as described in Example 25, and making variationas required to replace4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoicacid with4-((1-((3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.05 g,37%): ¹H NMR (300 MHz, CDCl₃) δ7.91 (d, J=7.5 Hz, 1H), 7.55 (d, J=7.8Hz, 1H), 7.52-7.35 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.47 (d, J=11.3 Hz,1H), 5.38-4.97 (br. s, 2H), 4.74-4.60 (m, 3H), 3.93-3.68 (m, 4H),3.50-3.39 (m, 2H), 3.21-3.06 (m, 3H), 2.44-1.78 (m, 10OH), 0.97-0.78 (m,2H), 0.60-0.48 (m, 2H); MS (ES+) m/z 585.1, 583.1 (M+1).

Example 30 Synthesis of(5)-1-(5-chloro-4-((3-chloro-4-(trifluoromethoxy)phenoxy)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(5-chloro-4-((3-chloro-4-(trifluoromethoxy)-phenoxy)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-chloro-4-((3-chloro-4-(trifluoromethoxy)phenoxy)methyl)-2-fluorobenzoicacid, the title compound was obtained as a colorless syrup (0.42 g,92%): ¹H NMR (300 MHz, CDCl₃) δ7.48 (d, J=5.8 Hz, 0.7H), 7.38 (d, J=5.9Hz, 0.3H), 7.32-7.22 (m, 2H), 7.07-7.05 (m, 1H), 6.88-6.82 (m, 1H),5.09-5.07 (m, 2H), 4.50 (dd, J=8.5, 4.4 Hz, 0.7H), 4.15-4.10 (m, 0.3H),3.83-3.68 (m, 0.6H), 3.55-3.47 (m, 0.7H), 3.42-3.35 (m, 0.7H), 2.33-2.23(m, 1H), 2.06-1.85 (m, 3H), 1.47 (s, 6H), 1.28 (s, 3H); MS (ES+) m/z553.9, 552.2 (M+1).

Step 2. Preparation of(S)-1-(5-chloro-4-((3-chloro-4-(trifluoromethoxy)phenoxy)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2 and makingvariations as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(5-chloro-4-((3-chloro-4-(trifluoromethoxy)phenoxy)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.38 g, quant.yield): ¹H NMR (300 MHz, CDCl₃) δ7.56 (br s, 1H), 7.51 (d, J=5.8 Hz,1H), 7.36 (d, J=9.8 Hz, 1H), 7.24 (s, 1H), 7.08 (d, J=3.0 Hz, 1H), 6.87(dd, J=9.0, 3.0 Hz, 1H), 5.10 (s, 2H), 4.71 (dd, J=7.6, 5.3 Hz, 1H),3.56-3.43 (m, 2H), 2.36-2.24 (m, 2H), 2.11-1.91 (m, 2H); MS (ES−) m/z495.9, 493.9 (M−1).

Example 31 Synthesis of(S)-1-(5-chloro-4-(((1S,3S,5S,7S)-2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(5-chloro-4-(((1S,3S,5S,7S)-2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-chloro-4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless foam (0.37 g, 83%):¹H NMR (300 MHz, CDCl₃) δ7.47 (d, J=7.0 Hz, 0.7H), 7.36 (d, J=7.0 Hz,0.3H), 6.68 (d, J=10.5 Hz, 0.7H), 6.67 (d, J=10.5 Hz, 0.3H), 4.49 (dd,J=4.8, 8.4 Hz, 0.7H), 4.28 (s, 2H), 4.16-4.12 (m, 0.3H), 3.79-3.70 (m,0.6H), 3.56-3.47 (m, 0.7H), 3.43-3.35 (m, 0.7H), 2.36-2.22 (m, 5H),2.02-1.73 (m, 13H), 1.47 (s, 6H), 1.31 (s, 3H); MS (ES+) m/z 517.0,519.0 (M+1).

Step 2. Preparation of(S)-1-(5-chloro-4-(((1S,3S,5S,7S)-2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2 and makingvariations as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(5-chloro-4-(((1S,3S,5S,7S)-2-cyanoadamantan-2-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a 1:1 complex with trifluoroaceticacid as a colorless solid (0.38 g, 97%): ¹H NMR (300 MHz, CDCl₃) 57.93(br s, 2H), 7.48 (d, J=7.0 Hz, 1H), 6.72 (d, J=10.7 Hz, 1H), 4.72-4.68(m, 1H), 4.30 (s, 2H), 3.59-3.46 (m, 2H), 2.35-2.27 (m, 6H), 2.11-1.74(m, 12H); MS (ES+) m/z 462.9, 460.9 (M+1).

Example 32 Synthesis of(S)-1-(4-(((1S,3S,5S,7S)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(4-(((1S,3S,5S,75)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1 and makingvariations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a colorless foam (0.36 g, 90%):¹H NMR (300 MHz, CDCl₃) δ6.97 (d, J=7.7 Hz, 0.7H), 6.90 (d, J=7.8 Hz,0.3H), 6.53 (d, J=11.2 Hz, 0.7H), 6.50 (d, J=11.1 Hz, 0.3H), 4.48 (dd,J=5.0, 8.4 Hz, 0.7H), 4.24 (s, 2H), 4.20-4.16 (m, 0.3H), 3.77-3.71 (m,0.6H), 3.55-3.47 (m, 0.7H), 3.41-3.33 (m, 0.7H), 2.36-2.24 (m, 5H),2.08-1.73 (m, 14H), 1.47 (s, 6H), 1.27 (s, 3H), 0.92-0.84 (m, 2H),0.63-0.55 (m, 2H); MS (ES+) m/z 523.2 (M+1).

Step 2. Preparation of(S)-1-(4-(((1S,3S,5S,7S)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2 and makingvariations as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-(((1S,3S,5S,7S)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a 1:1 complex with trifluoroaceticacid as a colorless solid (0.31 g, 81%): ¹H NMR (300 MHz, CDCl₃) δ 8.48(br s, 2H), 6.98 (d, J=7.7 Hz, 1H), 6.56 (d, J=11.3 Hz, 1H), 4.72-4.68(m 1H), 4.26 (s, 2H), 3.53-3.45 (m, 2H), 2.39-2.24 (m, 6H), 2.09-1.74(m, 13H), 0.95-0.84 (m, 2H), 0.64-0.59 (m, 2H); MS (ES+) m/z 467.0(M+1).

Example 33 Synthesis of(S)-1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-H-pyrazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoicacid and to replace (S)-tert-butyl pyrrolidine-2-carboxylatehydrochloride with (S)-methyl pyrrolidine-2-carboxylate hydrochloride,the title compound was obtained as an colorless foam (0.29 g, 94%): ¹HNMR (300 MHz, CDCl₃) δ 7.61-7.58 (m, 1H), 7.41-7.35 (m, 1H), 7.33-7.30(m, 1H), 7.25-7.18 (m, 1H), 6.91-6.86 (m, 1H), 6.56-6.50 (m, 1H),6.25-6.23 (m, 1H), 4.94-4.85 (m, 1H), 4.62-4.56 (m, 1H), 4.41-4.33 (m,2H), 4.27-4.19 (m, 2H), 3.73 (s, 3H), 3.52-3.33 (m, 1H), 2.35-2.18 (m,1H), 2.10-1.81 (m, 4H), 1.40 (s, 9H),

Step 2. Preparation of(S)-1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylicacid

To a solution of (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylate(0.29 g, 0.47 mmol) in tetrahydrofuran (20 mL) and water (4 mL) wasadded lithium hydroxide (0.02 g, 0.83 mmol). The reaction mixture wasstirred at ambient temperature for 20 hours, and then concentrated invacuo to remove most of tetrahydrofuran. The residue was acidified topH˜1 with 5% hydrochloric acid solution. The solid was collected byfiltration and washed with water and dried to give the title compound asan colorless solid (0.22 g, 77%): ¹H NMR (300 MHz, CDCl₃) δ 7.68-7.60(m, 1H), 7.43-7.32 (m, 2H), 7.29-7.21 (m, 1H), 6.96-6.79 (m, 2H),6.31-6.22 (m, 1H), 4.94-4.80 (m, 1H), 4.70-4.62 (m, 1H), 4.44-4.18 (m,4H), 3.88-3.36 (m, 2H), 2.44-1.87 (m, 4H), 1.40 (s, 9H); (ES−) m/z601.2, 603.2 (M−1).

Example 34 Synthesisof(S)-1-(4-(2-(1-(azetidin-3-yl)-1H-pyrazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith(S)-1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylicacid, the title compound was obtained as a colorless solid (0.07 g,54%): ¹H NMR (300 MHz, DMSO-d₆) δ 10.01-8.94 br s, 2H), 7.81-7.72 (m,1H), 7.66-7.55 (m, 2H), 7.49-7.32 (m, 1H), 7.29-7.12 (m, 2H), 6.55-6.40(m, 1H), 5.35-4.97 (m, 1H), 4.47-3.98 (m, 5H), 3.58-3.50 (m, 2H),2.35-2.16 (m, 1H), 2.02-1.73 (m, 3H); MS (ES−) m/z 501.0, 503.0 (M−1).

Example 35 Synthesis of2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido) aceticacid

Step 1. Preparation of tert-butyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)acetate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with tert-butyl 2-aminoacetate,the title compound was obtained as colorless solid (0.71 g, 76%): ¹H NMR(300 MHz, DMSO-d₆) δ 7.60 (d, J=9.1 Hz, 1H), 7.21-7.13 (m, 1H), 6.52 (d,J=14.2 Hz, 1H), 4.14 (d, J=4.2 Hz, 2H), 3.53 (s, 2H), 2.10-2.03 (m, 4H),1.80-1.69 (m, 12H), 1.50 (s, 9H), 0.94-0.87 (m, 2H), 0.70-0.65 (m, 2H);MS (ES+) m/z 458.2 (M+1).

Step 2. Preparation of2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido) aceticacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)acetate,the title compound was obtained as colorless solid: (0.19 g, 31%): ¹HNMR (300 MHz, DMSO-d₆) δ12.65 (s, 1H), 8.20-8.14 (m, 1H), 7.23 (d, J=8.7Hz, 1H), 6.89 (d, J=13.4 Hz, 1H), 3.88 (d, J=5.7 Hz, 2H), 3.63 (s, 3H),2.09-1.99 (m, 4H), 1.75-1.67 (m, 12H), 0.94-0.87 (m, 2H), 0.63-0.58 (m,2H); MS (ES+) m/z 402.1 (M+1); MS (ES−) m/z 400.2 (M−1).

Example 36 Synthesis of1-(5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzamido)-cyclopropanecarboxylicacid

Step 1. Preparation of tert-butyl1-(5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzamido)cyclopropanecarboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzoic acid,and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withtert-butyl 1-aminocyclopropanecarboxylate, the title compound wasobtained as colorless solid (0.60 g, 90%): ¹H NMR (300 MHz, DMSO-d₆)δ8.17 (d, J=7.8 Hz, 1H), 7.33-7.29 (m, 1H), 7.15-7.10 (m, 2H), 6.92 (dd,J=2.9 Hz, 9.0 Hz, 1H), 6.68 (d, J=11.9 Hz, 1H), 3.66 (s, 3H), 1.65-1.61(m, 2H), 1.25-1.21 (m, 2H); MS (ES+) m/z 481.9, 483.9 (M+1); MS (ES−)m/z 480.0, 482.0 (M−1).

Step 2. Preparation of1-(5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzamido)cyclopropanecarboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl1-(5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzamido)cyclopropanecarboxylate,the title compound was obtained as colorless solid (0.31 g, 99%): ¹H NMR(300 MHz. DMSO-d₆) δ12.49 (s, 1H), 8.92 (s, 1H), 7.81 (d, J=7.2 Hz, 1H),7.63-7.60 (m, 1H), 7.49 (d, J=3.0 Hz, 1H), 7.33 (d, J=10.6 Hz, 1H), 7.15(dd, J=3.0 Hz, 9.1 Hz, 1H), 1.43-1.38 (m, 2H), 1.14-1.10 (m, 2H); MS(ES+) m/z 467.8, 469.8 (M+1); MS (ES−) m/z 465.9, 467.9 (M−1).

Example 37 Synthesis of(S)-1-(5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzoyl)-pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzoic acid,the title compound was obtained as colorless oil (0.17 g, 67%): MS (ES+)m/z 538.0, 540.0 (M+1); MS (ES−) m/z 480.0, 482.0 (M−1).

Step 2. Preparation of(S)-1-(5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(5-chloro-4-(3-chloro-4-(trifluoromethoxy)phenoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as colorless solid (0.14 g, 91%): ¹H NMR(300 MHz, CDCl₃) δ7.61 (d, J=6.7 Hz, 1H), 7.34-7.31 (m, 1H), 7.12 (d,J=2.9 Hz, 1H), 6.93 (dd, J=2.9 Hz, 9.0 Hz, 1H), 6.73 (d, J=9.8 Hz, 1H),4.70 (t, J=6.3 Hz, 1H), 3.54-3.48 (m, 2H), 2.33-2.26 (m, 2H), 2.12-1.91(m, 2H) (OH proton not observed); MS (ES+) m/z 481.9, 483.9 (M+1); MS(ES−) m/z 480.0, 482.0 (M−1).

Example 38 Synthesisof(S)-1-(4-(((R)-1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Step 1. Preparation of (S)-tert-butyl1-(4-(((R)-1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with(R)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as colorless oil (0.18 g, 67%): MS(ES+) m/z 575.2, 577.2 (M+1).

Step 2. Preparation of(S)-1-(4-(((R)-1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-(((R)-1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as colorless solid (0.12 g, 72%): ¹H NMR(300 MHz, DMSO-d₆+drop D₂O at 60° C.) δ7.76 (dd, J=6.2 Hz, 8.7 Hz, 1H),7.53 (dd, J=2.6 Hz, 8.8 Hz, 1H), 7.32 (dt. J=2.7 Hz, 8.5 Hz, 1H),6.98-6.72 (m, 2H), 4.74-4.73 (m, 1H), 4.45 (s, 2H), 4.41-4.37 (m, 0.7H),4.11-4.07 (m, 0.3H), 3.53-3.48 (m, 2H), 3.34-3.23 (m, 4H), 2.32-1.80 (m,9H), 0.90-0.88 (m, 2H), 0.61-0.60 (m, 2H); MS (ES+) m/z 519.1, 521.1(M+1).

Example 39 Synthesis of(2S)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Step 1. Preparation of (2S)-tert-butyl1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as colorless oil (0.60 g, 52%): MS(ES+) m/z 619.2, 621.2 (M+1).

Step 2. Preparation of(2S)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (2S)-tert-butyl1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as colorless solid (0.27 g, 57%): ¹H NMR(300 MHz, CDCl₃) δ11.21-10.82 (m, 1H), 7.44-7.37 (m, 3H), 6.90-6.79 (m,1H), 6.47-6.38 (m, 1H), 4.65-4.61 (m, 1H), 4.45-4.27 (m, 1H), 3.82-3.72(m, 3H), 3.57-3.38 (m, 3H), 2.72-2.65 (m, 2H), 2.33-2.17 (m, 2H),2.05-1.75 (m, 11H), 0.85-0.76 (m, 2H), 0.51-0.48 (m, 2H), MS (ES+) m/z563.1, 565.0 (M+1).

Example 40 Synthesis of(S)-1-(4-(adamantan-1-ylmethoxy)-2-fluoro-5-methylbenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-2-fluoro-5-methylbenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-2-fluoro-5-methylbenzoic acid, the titlecompound was obtained as colorless oil (0.42 g, 95%): MS (ES+) m/z 472.2(M+1).

Step 2 Preparation of(S)-1-(4-(adamantan-1-ylmethoxy)-2-fluoro-5-methylbenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-2-fluoro-5-methylbenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as colorless solid (0.32 g, 87%): ¹H NMR(300 MHz, CDCl₃) δ 8.01 (br s, 1H), 7.21 (d, J=8.0 Hz, 0.7H), 7.12 (d,J=8.5 Hz, 0.3H), 6.60 (d, J=11.3 Hz, 0.3H), 6.52 (d, J=12.0 Hz, 0.7H),4.79-4.71 (m, 1H), 3.589-3.38 (m, 4H), 2.60-2.40 (m, 1H), 2.20-2.13 (m,4H), 2.03-1.88 (m, 5H), 1.80-1.57 (m, 12H); MS (ES+) m/z 416.0 (M+1); MS(ES−) m/z 414.1 (M−1).

Example 41 Synthesis of(S)-1-(4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid, the titlecompound was obtained as colorless solid (0.24 g, 65%): ¹H NMR (300 MHz,CDCl₃) δ7.41 (d, J=7.1 Hz, 0.7H), 7.30 (d, J=7.1 Hz, 0.3H), 6.62-6.56(m, 1H), 4.48-4.44 (m, 0.7H), 4.16-4.13 (m, 0.3H), 3.76-3.69 (m, 0.7H),3.54-3.46 (m, 0.6H), 3.50 (s, 2H), 3.42-3.34 (m, 0.7H), 2.31-2.20 (m,1H), 2.07-1.86 (m, 6H), 1.78-1.66 (m, 12H), 1.45 (s, 6.5H), 1.29 (s,2.5H); MS (ES+) m/z 492.1, 494.1 (M+1).

Step 2. Preparation of(S)-1-(4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as colorless solid (0.18 g, 88%): ¹H NMR(300 MHz, CDCl₃) δ7.46 (d, J=7.1 Hz, 0.9H), 7.35 (d, J=7.1 Hz, 0.1H),6.65-6.57 (m, 1H), 5.29 (br s, 1H), 4.71-4.67 (m, 0.9H), 4.35-4.31 (m,0.1H), 3.79-3.72 (m, 0.2H), 3.52 (s, 2H), 3.50-3.46 (m 1.8H), 2.42-2.15(m, 2H), 2.07-1.86 (m, 5H), 1.78-1.66 (m, 12H); MS (ES+) m/z 436.0,438.0 (M+1); MS (ES−) m/z 434.1, 436.1 (M−1).

Example 42 Synthesis ofcis-(S)-1-(5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)-cyclohexyl)methoxy)benzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of cis-(S)-tert-butyl1-(5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)methoxy)benzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid withcis-5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)methoxy)benzoicacid, the title compound was obtained as colorless solid (0.43 g, 87%):MS (ES+) m/z 528.1 (M+1), 472.1 (M−55).

Step 2. Preparation ofcis-(S)-1-(5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)methoxy)benzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith cis-(S)-tert-butyl1-(5-cyclopropyl-2-fluoro-4-((1-methyl-4-(trifluoromethyl)cyclohexyl)methoxy)benzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as colorless solid (0.40 g, 95%): ¹H NMR(300 MHz, CDCl₃) δ7.93 (br s, 1H), 7.00 (d, J=7.8 Hz, 1H), 6.57 (d,J=11.8 Hz, 1H), 4.75-4.71 (m, 1H), 3.80 (s, 2H), 3.57-3.42 (m, 2H),2.49-2.39 (m, 1H), 2.26-2.14 (m, 1H), 2.10-1.80 (m, 8H), 1.55-1.41 (m,2H), 1.34-1.25 (m, 2H), 1.11 (s, 3H), 0.93-0.87 (m, 2H), 0.64-0.59 (m,2H); MS (ES+) m/z 472.1 (M+1); MS (ES−) m/z 470.0 (M−1).

Example 43 Synthesis of(2S,3S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-methylpentanoicacid

Step 1. Preparation of (2S,3S)-tert-butyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-methylpentanoate

Following the procedure as described in Example 1 step 1, and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with (2S,3S)-tert-butyl2-amino-3-methylpentanoate hydrochloride, the title compound wasobtained as colorless oil (0.27 g, 76%): ¹H NMR (300 MHz, CDCl₃) δ7.58(d, J=9.1 Hz, 1H), 7.25-7.18 (m, 1H), 6.50 (d, J=14.2 Hz, 1H), 4.72-4.67(m, 1H), 3.51 (s, 2H), 2.08-1.92 (m, 5H), 1.77-1.67 (m, 12H), 1.60-1.50(m, 1H), 1.29-1.19 (m, 1H), 0.98-0.85 (m 9H), 0.68-0.63 (m, 2H),

Step 2. Preparation of (2S3S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-methylpentanoicacid

Following the procedure as described in Example 1 step 2, and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (2S,3S)-tert-butyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-methylpentanoate,the title compound was obtained as colorless solid (0.25 g, 95%): ¹H NMR(300 MHz, CDCl₃) δ7.58 (d, J=9.2 Hz, 1H), 7.27 (br s, 1H), 7.20-7.12 (m,1H), 6.52 (d, J=14.3 Hz, 1H), 4.82-4.77 (m, 1H), 3.53 (s, 2H), 2.12-2.04(m, 5H), 1.80-1.49 (m, 13H), 1.35-1.20 (m, 1H), 1.03-0.87 (m 8H),0.69-0.64 (m, 2H), MS (ES+) m/z 458.1 (M+1); MS (ES−) m/z 456.2 (M−1).

Example 44 Synthesis of(S)-1-(5-chloro-4-(((6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Step 1. Preparation of(S)-1-(5-chloro-4-(((6,6-difluorobicyclo[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 46, and makingvariations as required to replace6-adamantan-1-ylmethoxy)-5-chloronicotinic acid with5-chloro-4-6,6-difluorobicyclo-[3.1.0]hexan-3-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as an colorless solid (0.25 g, 63%in two steps): ¹H NMR (300 MHz, CDCl₃) δ (d, J=7.0 Hz, 1H), 6.64 (d,J=11.1 Hz, 1H), 4.72-4.68 (m, 1H), 3.91 (d, 0.1=5.9 Hz, 2H), 3.50 (t,J=6.8 Hz, 1H), 2.63-2.44 (m, 1H), 2.42-2.15 (m, 4H), 2.12-1.85 (m, 7H),MS (ES+) m/z 418.0 (M+1).

Example 45 Synthesis of2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-methylbenzamido)aceticacid

Step 1. Preparation of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl chloride

To a stirred suspension of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid (2.06 g,5.98 mmol) in dichloromethane (30 mL) was added oxalyl chloride (1.04mL, 11.90 mmol), followed by a drop of N,N-dimethyl formamide, and thereaction mixture was stirred at ambient temperature for 140 minutes. Thesolution was concentrated, and azeotropic removal of oxalyl chlorideusing dichloromethane (20 mL) provided the title compound as a palesolid (2.19 g, quant. yield): ¹H NMR (300 MHz, CDCl₃) δ7.63 (d, J=8.3Hz, 1H), 6.57 (d, J=12.8 Hz, 1H), 3.57 (s, 2H), 2.05-1.98 (m, 4H),1.81-1.69 (m, 12H), 1.00-0.93 (m, 2H), 0.69-0.63 (m, 2H),

Step 2. Preparation of ethyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-methylbenzamido)acetate

To a solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoylchloride (0.30 g, 0.83 mmol) in dichloromethane (4 mL) was added to amixture of sarcosine ethyl ester hydrochloride (0.19 g, 1.24 mmol) andtriethylamine (0.4 mL, 2.90 mmol) in dichloromethane (4.3 mL). Afterstirring at ambient temperature for 16 hours, the reaction mixture wasconcentrated in vacuo. The residue was partitioned between ethyl acetate(40 mL) and 1.0 N hydrochloric acid solution (15 mL). The organic layerwas washed with saturated aqueous sodium bicarbonate solution (15 mL×2)and brine (15 mL×2); dried over anhydrous magnesium sulfate andconcentrated in vacuo. Purification of the residue by columnchromatography (0% to 20% ethyl acetate in hexanes) provided the titlecompound as a colorless foam (0.34 g, 92%): ¹H NMR (300 MHz, CDCl₃)δ6.95 (d, J=7.8 Hz, 0.7H), 6.87 (d, J=7.9 Hz, 0.3H), 6.53-6.48 (m, 1H),4.27-4.16 (m 3.3H), 3.95 (s, 0.7H), 3.51 (m, 2H), 3.12 (s, 1H), 3.00 (m,2H), 2.07-2.03 (m 4H), 1.80-1.69 (m, 12H), 1.33-1.23 (m, 3H), 0.93-0.85(m, 2H), 0.66-0.55 (m, 2H),

Step 3. Preparation of2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-methylbenzamido)aceticacid

To a solution of ethyl2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluoro-N-methylbenzamido)acetate(0.33 g, 0.74 mmol) in tetrahydrofuran (6 mL) was added a solution oflithium hydroxide monohydrate (0.05 g, 1.10 mmol) in water (1.5 mL).After stirring at ambient temperature for 3 days, the reaction mixturewas diluted with diethyl ether (20 mL) and washed with 1 N hydrochloricacid solution (15 mL). The aqueous layer was extracted with diethylether (15 mL); the combined organic layers were dried over anhydrousmagnesium sulfate and concentrated in vacuo. Purification of the residueby recrystallization (acetonitrile) provided the title compound ascolorless solid (0.29 g, 93%): ¹H NMR (300 MHz, DMSO-d₆) δ12.81 (br s,1H), 6.89-6.83 (m, 1H), 6.79 (d, J=7.9 Hz, 0.6H), 6.68 (d, J=7.9 Hz,0.4H), 4.12 (s, 1.2H), 3.88 (s, 0.8H), 3.60-3.58 (m, 2H), 2.96 (s,1.2H), 2.87-2.86 (m, 1.8H), 2.06-1.99 (m, 4H), 1.75-1.66 (m, 12H),0.93-0.85 (m, 2H), 0.63-0.51 (m, 2H), MS (ES+) m/z 416.1 (M+1).

Example 46 Synthesis of(2S,4S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4-hydroxy-pyrrolidine-2-carboxylicacid

Step 1. Preparation of4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride

Thionyl chloride (1105 mg, 9.29 mmol) was added to a suspension of4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoic acid (800 mg, 2.32mmol) in dichloromethane (5 ml). 0.5 ml of DMF was added and the mixturewent onto solution. The mixture was stirred for 15 min and thenconcentrated to afford 815 mg (97%) of4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride as a paleyellow solid. The compound was carried on to next step withoutpurification.

Step 2. Preparation of(2S,4S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4-hydroxy-pyrrolidine-2-carboxylicacid

Trifluoroacetic acid (0.49 mL, 6.49 mmol) was added to a solution of(2s,4s)-1-tert-butoxycarbonyl-4-fluoro-pyrrolidine-2-carboxylic acid(150 mg, 0.65 mmol) in dichloromethane (3 ml) and the mixture wasstirred at room temperature for 30 minutes. The mixture was thenconcentrated. The residue was taken up in dichloromethane (2 mL) andN,N-diisopropylethylamine (0.57 mL, 3.24 mmol) was added. Then, asolution of 4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoylchloride (247 mg, 0.68 mmol), dissolved in dichloromethane (5 ml) wasadded slowly. The mixture was stirred at room temperature for 20 min andthen concentrated. The residue was purified by reverse phase HPLC(method) to afford 171 mg (57%) of(2S,4S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4-hydroxy-pyrrolidine-2-carboxylicacid as a white solid. LCMS (Method Waters, ESI); RT=7.1 min, m+H=458.4.¹H NMR (400 MHz, DMSO-d₆) δ 6.88-6.77 (m, 2H), 6.77-6.71 (m, 2H), 4.26(dd, J=9.0, 4.4 Hz, 1H), 4.12 (dq, J=14.1, 4.7 Hz, 2H), 3.83 (d, J=9.1Hz, 1H), 3.65-3.53 (m, 5H), 3.15 (dd, J=10.5, 3.9 Hz, 1H), 2.28 (td,J=8.7, 4.5 Hz, 1H), 2.22-2.13 (m, 1H), 2.08-1.94 (m, 4H), 0.94-0.79 (m,4H), 0.68-0.53 (m, 1H),

The compounds of Examples 47-50 were prepared using procedures similarto those described above.

Example 47 Synthesis of(2R,4R)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4-hydroxy-pyrrolidine-2-carboxylicacid

LCMS (Method Waters, ESI): RT=7.1 min, 333+H=458.4.

Example 48 Synthesis of(2S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid

LCMS (Method Waters, ESI): RT=7.9 min, m+H=478.2.

Example 49 Synthesis of(2S,4R)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4-fluoro-pyrrolidine-2-carboxylicacid

LCMS (Method Waters, ESI): RT=7.7 min, m+H=461.2

Example 50 Synthesis of(4S)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]thiazolidine-4-carboxylicacid

LCMS (Method Waters, ESI): RT=7.9 min, m+H=460.2

Example 51 Synthesis of(S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-2-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-2-methylpyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with 2-methyl-L-proline methylester hydrochloride, the title compound was obtained as a colorless foam(0.45 g, 87%): ¹H NMR (300 MHz, CDCl₃) δ 6.88 (d, J=7.8 Hz, 1H), 6.46(d, J=12.0 Hz, 1H), 3.72 (s, 3H), 3.51-3.40 (m, 4H), 2.20-2.14 (m, 1H),2.05-1.81 (m, 5H), 1.77-1.62 (m, 17H), 0.87-0.80 (m, 2H), 0.63-0.55 (m,2H),

Step 2. Preparation of(S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-2-methylpyrrolidine-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropanecarboxylatewith(S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-2-methylpyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.31 g, 78%): ¹HNMR (300 MHz, CDCl₃) δ 6.95 (d, J=7.8 Hz, 1H), 6.49 (d, J=12.3 Hz, 1H),3.66-3.45 (m, 3H), 3.42-3.31 (m, 1H), 2.06-1.97 (m, 4H), 2.86-2.75 (m,1H), 2.12-1.96 (m, 2H), 1.87-1.61 (m, 17H), 0.96-0.80 (m, 2H), 0.65-0.58(m, 2H); MS (ES+) m/z: 456.1 (M+1).

Example 52 Synthesis of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3,3-dimethylbutanoicacid Step 1. Preparation of tert-butyl(S)-2-(4-(adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzamido)-3,3-dimethylbutanoate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with tert-butyl(S)-2-amino-3,3-dimethylbutanoate hydrochloride, the title compound wasobtained as a colorless foam (0.20 g, 78%): ¹H NMR (300 MHz, CDCl₃) δ7.55 (d, J=9.0 Hz, 1H),7.22-7.10 (m, 1H), 6.49 (d, J=14.4 Hz, 1H),4.55-4.50 (m, 1H), 3.48 (s, 2H), 2.05-1.92 (m 4H), 1.75-1.62 (m, 12H),1.43 (s, 9H), 0.99 (s, 9H), 0.90-0.82 (m, 2H), 0.66-0.60 (m, 2H),

Step 2. Preparation of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3,3-dimethylbutanoicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropanecarboxylatewith tert-butyl(S)-2-(4-(adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzamido)-3,3-dimethylbutanoate,the title compound was obtained as a colorless solid (0.31 g, 78%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.76 (br s, 1H), 7.70-7.64 (m, 1H), 7.13 (d,J=8.7 Hz, 1H), 6.85 (d, J=13.5 Hz, 1H), 4.27 (d, J=9.0 Hz, 1H), 3.59 (s,2H), 2.05-1.89 (m, 4H), 1.75-1.58 (m, 12H), 0.96 (s, 9H), 0.90-0.83 (m,2H), 0.59-0.53 (m, 2H), MS (ES+) m/z 458.1 (M+1).

Example 53 Synthesis of(2S)-2-cyclopropyl-2-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzamido)aceticacid Step 1. Preparation of methyl(2S)-2-cyclopropyl-2-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzamido)acetate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoicacid, and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (S)-2-amino-2-cyclopropylacetate hydrochloride, the titlecompound was obtained as a colorless foam (0.30 g, 48%): ¹H NMR (300MHz, CDCl₃) δ 7.60-7.48 (m, 1H), 7.38-7.23 (m, 3H), 7.17-7.09 (m, 1H),6.49 (d, J=14.1 Hz, 1H), 4.21 (s, 1H), 4.19-4.02 (m, 1H), 3.84-3.73 (m,4H), 3.08-2.92 (m, 2H), 2.50-2.30 (m, 2H), 2.07-1.95 (m, 2H), 2.03-1.78(m, 4H),1.53-1.40 (m, 2H), 0.91-0.82 (m, 2H), 0.67-0.42 (m, 6H),

Step 2. Preparation of(2S)-2-cyclopropyl-2-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzamido)aceticacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-cyclopropanecarboxylatewith methyl(2S)-2-cyclopropyl-2-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzamido)acetate,the title compound was obtained as a colorless solid (0.11 g, 37%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.56 (br s, 1H), 8.15-8.10 (m, 1H), 7.69-7.67(m, 1H), 7.42 (s, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.84 (d, J=13.2 Hz, 1H),4.79-4.68 (m, 1H), 3.88-3.06 (m, 3H), 2.97 (br s, 2H), 2.32-2.20 (m,1H), 2.07-1.95 (m, 2H), 1.58-1.52 (m, 3H),1.38-1.05 (m, 4H), 0.32-0.89(m, 2H), 0.59-0.26 (m, 6H); MS (ES+) m/z 617.1, 619.1 (M+1).

Example 54 Synthesis of((S)-2-(1H-tetrazol-5-yl)pyrrolidin-1-yl)(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorophenyl)methanoneStep 1. Preparation of(S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carbonitrile

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with(S)-pyrrolidine-2-carbonitrile hydrochloride, the title compound wasobtained as a colorless foam (1.04 g, 60%): ¹H NMR (300 MHz, CDCl₃) δ6.97 (d, J=8.1 Hz, 1H), 6.49 (d, J=12.0 Hz, 1H), 4.86-4.81 (m, 1H),3.55-3.37 (m, 4H), 2.35-1.96 (m, 7H), 1.79-1.64 (m, 13H), 0.93-0.85 (m,2H), 0.65-0.58 (m, 2H); MS (ES+) m/z 423.1 (M+1).

Step 2. Preparation of((S)-2-(1H-tetrazol-5-yl)pyrrolidin-1-yl)(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorophenyl)methanone

To a solution of(S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-pyrrolidine-2-carbonitrile(0.42 g, 1.00 mmol) in N,N-dimethylformamide (20 mL) was added sodiumazide (1.30 g, 20.00 mmol) and ammonium chloride (1.08 g, 20.00 mmol).The resulting mixture was heated at 100° C. for 18 hours. The reactionwas cooled to ambient temperature, followed by addition of water (10.0mL) and extraction with ethyl acetate (50 mL×3), the combined organicphase was washed with water and brine; dried over anhydrous sodiumsulfate and concentrated in vacuo. The residue was purified by columnchromatography eluting with ethyl acetate to afford the title compoundas a colorless solid (0.35 g, 75%): ¹H NMR (300 MHz, CDCl₃) δ 6.90 (d,J=7.8 Hz, 0.8H), 6.83 (d, J=12.0 Hz, 0.8H), 6.67 (d, J=12.0 Hz, 0.2H),6.39 (d, J=7.8 Hz, 0.2H), 5.39-5.34 (m, 0.8H), 5.06-5.01 (m, 0.2H),3.75-3.41 (m, 4H), 2.41-2.28 (m, 1H), 2.06-1.80 (m, 7H), 1.71-1.58 (m,12H), 0.89-0.84 (m, 2H), 0.61-0.55 (m, 2H), MS (ES+) m/z: 466.1 (M+1).

Example 55 Synthesis of(5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzoyl)-L-prolineStep 1. Preparation of tert-butyl(5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless foam (0.19 g, 94%):MS (ES+) m/z 522.3 (M+1).

Step 2. Preparation of(5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzoyl)-L-proline

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace tert-butyl(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinatewith of tert-butyl(5-cyclopropyl-4-((1,1-difluoro-6-methylspiro[2.5]octan-6-yl)methoxy)-2-fluorobenzoyl)-L-prolinateand following the residue was purified by reverse-phase HPLC, the titlecompound was obtained as a colorless solid (0.073 g, 44%): ¹H NMR (300MHz, CDCl₃) δ 7.00 (d, J=7.8 Hz, 1H), 6.56 (d, J=11.9 Hz, 1H), 6.54 (d,J=11.9 Hz, rotomer), 4.73 (dd, J=4.2, 8.1 Hz, 1H), 3.80-3.67 (m, 2H),3.56-3.40 (m, 2H), 2.54-2.40 (m, 1H), 2.26-2.10 (m, 1H), 2.08-1.86 (m,3H), 1.82-1.38 (m, 8H), 1.13 (s, 3H), 1.15 (s, rotomer), 1.07-0.97 (m,2H), 0.99-0.83 (m, 2H), 0.65-0.57 (m, 2H); MS (ES+) m/z 466.1, 467.1,(ES−) m/z 464.2, 465.2.

Example 56 Synthesis(5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[2.2.2]octan-1-yl)methoxy)benzoyl)-L-prolineStep 1. Preparation of methyl 4-fluorobicyclo[2.2.2]octane-1-carboxylate

To a cooled (0° C.) solution of methyl4-hydroxybicyclo[2.2.2]octane-1-carboxylate (2.0 g, 10.86 mmol) andanhydrous methanol (0.08 mL, 1.63 mmol) in anhydrous chloroform (12 mL),2-chloro-N,N-diethyl-1,1,2-trifluoroethanamine (2.59 mL, 16.28 mmol) wasadded dropwise to minimize internal temperature. The resulting solutionwas heated at 60° C. for 24 h. The solution was cooled to ambienttemperature and diluted with dichloromethane (50 mL) and water (50 mL).The aqueous layer was separated and extracted with dichloromethane (3×50mL). The combined organic layers were washed with brine (30 mL), driedover anhydrous sodium sulfate, filtered and concentrated. The residuewas purified using flash chromatography eluting with gradient 0° % to10% of ethyl acetate in hexanes to afford the title compound ascolorless liquid (1.67 g, 83%): ¹H NMR (300 MHz, CDCl₃) δ 3.64 (s, 3H),2.05-1.96 (m, 6H), 1.86-1.79 (m, 6H),

Step 2. Preparation of (4-fluorobicyclo[2.2.2.2]octan-1-yl)methanol

To a cooled (0° C.) suspension of lithium aluminum hydride (1.34 g, 35.9mmol) in anhydrous diethyl ether (50 mL) was added a solution of methyl4-fluorobicyclo[2.2.2]octane-1-carboxylate (1.67 g, 8.97 mmol) inanhydrous diethyl ether (30 mL). The reaction was slowly warmed toambient temperature and stirred overnight. The reaction was cooled at 0°C. and carefully quenched with water (1.4 mL) then diluted with diethylether (50 mL). The precipitate was removed by filtration and thefiltrate was concentrated in vacuo to afford the title compound as acolorless liquid (1.33 g, 93%) which was used without furtherpurification: ¹H NMR (300 MHz. CDCl₃) δ 3.28 (s, 2H), 1.88-1.78 (m, 6H),1.68-1.56 (m, 6H), 1.56-1.37 (br s, 1H),

Step 3. Preparation tert-butyl5-chloro-2-fluoro-4-((4-fluorobicyclo[22.2]octan-1-yl)-methoxy)benzoate

A suspension of (4-fluorobicyclo[2.2.2]octan-1-yl)methanol (0.180 g,1.14 mmol), tert-butyl 5-chloro-2,4-difluorobenzoate (0.296 g, 1.19mmol) and cesium carbonate (0.743 g, 2.28 mmol) in anhydrous dimethylsulfoxide (4 mL) was heated at 80° C. and stirred overnight. Thesolution was quenched with 1 N aqueous hydrochloric acid (10 mL) anddiluted with saturated aqueous ammonium chloride (50 mL) and ethylacetate (150 mL). The aqueous layer was separated and extracted withethyl acetate (3×100 mL). The combined organic layers were then washedwith brine (100 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified using flashchromatography eluting with gradient 0% to 5% of ethyl acetate inhexanes to afford the title compound as a colorless gum (0.27 g, 61%):¹H NMR (300 MHz, CDCl₃) δ 7.87 (d, J=7.6 Hz, 1H), 6.57 (d, J=12.1 Hz,1H), 3.62 (s, 2H), 1.94-1.78 (m, 12H), 1.57 (s, 9H),

Step 4. Preparation of tert-butyl5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[2.2.2]octan-1-yl)methoxy)benzoate

A suspension of tert-butyl5-chloro-2-fluoro-4-((4-fluorobicyclo[2.2.2]octan-1-yl)methoxy)benzoate(0.26 g, 0.48 mmol), cyclopropylboronic acid (0.089 g, 1.03 mmol),tricyclohexylphosphine tetrafluoroborate (0.026 g, 0.069 mmol),potassium phosphate (0.65 g, 3.08 mmol) in toluene (5.0 mL) and water(0.5 mL) was sparged with argon for 10 minutes before palladium acetate(0.008 g, 0.034 mmol) was added. The mixture was heated at 110° C. andstirred overnight. After cooling to ambient temperature, the reactionmixture was filtered through a Celite plug and rinsed with water (10mL), tetrahydrofuran (20 mL) and ethyl acetate (50 mL). The filtrate wasconcentrated and the residue was diluted with water (25 mL) and ethylacetate (50 mL). The aqueous layer was separated and extracted withethyl acetate (3×50 mL). The combined organics were dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The residue waspurified by flash chromatography eluting with gradient 0% to 10% ofethyl acetate in hexanes to afford the title compound as a colorless gum(0.255 g, 95%): MS (ES+) m/z 337.1, 338.1 (M+1).

Step 5. Preparation of5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[2.2.2]octan-1-yl)methoxy)benzoicacid

To a solution of tert-butyl5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[2.2.2]octan-1-yl)methoxy)benzoate(0.20 g, 0.51 mmol) in 1,4-dioxane (8 mL) was added 12M aqueoushydrochloric acid (2.10 mL, 25.5 mmol). The mixture was stirred atambient temperature overnight. The reaction was diluted withdichloromethane (100 mL) and water (50 mL). The aqueous layer wasseparated and extracted with dichloromethane (3×50 mL). The combinedorganics were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to afford the title compound as a gum (0.17 g,quantitative yield) which was used without further purification: ¹H NMR(300 MHz, DMSO-d₆) δ 12.82 (s, 1H), 7.31 (d, J=8.5 Hz, 1H), 6.85 (d,J=13.1 Hz, 1H), 3.71 (s, 2H), 2.08-1.95 (m, 1H), 1.85-1.73 (m, 12H),0.94-0.86 (m, 2H), 0.62-0.55 (m, 2H); MS (ES+) m/z 337.1, 338.1 (M+1).

Step 6. Preparation tert-butyl(5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[2.2.2]octan-1-yl)methoxy)benzoyl)-L-prolinate

A solution5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[2.2.2]octan-1-yl)methoxy)benzoicacid (0.167 g, 0.496 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.318 g, 0.992 mmol), hydroxybenzotriazole (0.087 g, 0.645 mmol) andN,N-diisopropylethylamine (0.345 mL, 1.98 mmol) in acetonitrile (12 mL)was stirred for 20 min then tert-butyl L-prolinate hydrochloride (0.123g, 0.595 mmol) was added in one portion. The reaction was stirred atambient temperature 16 h. The reaction was concentrated, diluted withethyl acetate (100 mL) and washed with 5% aqueous hydrochloric acid (20mL). The aqueous layer was separated and extracted with ethyl acetate(2×50 mL). The combined organics were washed with brine (20 mL), driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by flash chromatography eluting with gradient 0% to 10% ofethyl acetate in hexanes to the title compound as a colorless gum (0.22g, 92%): MS (ES+) m/z 490.3, 491.3 (M+1).

Step 7. Preparation of(5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[2.2.2]octan-1-yl)methoxy)benzoyl)-L-proline

To a solution tert-butyl(5-cyclopropyl-2-fluoro-4-((4-fluorobicyclo[2.2.2]octan-1-yl)methoxy)benzoyl)-L-prolinate(0.22 g, 0.46 mmol) in 1,4-dioxane (7 mL) was added 12 M aqueoushydrochloric acid (1.9 mL, 22.8 mmol). The reaction was stirred atambient temperature overnight. The reaction was diluted withdichloromethane (100 mL) and water (50 mL). The aqueous layer wasseparated and extracted with dichloromethane (3×50 mL). The combinedorganics were dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by reverse-phase HPLC toafford the title compound as colorless solid (0.17 g, 87%): ¹H NMR (300MHz, CDCl₃) δ 6.97 (d, J=7.8 Hz, 1H), 6.49 (d, J=11.8 Hz, 1H), 4.72 (dd,J=4.2, 8.1 Hz, 1H), 3.71 (s, 2H), 3.58 (s, 1H), 3.55-3.39 (m, 2H),2.52-2.39 (m, 1H), 2.26-2.10 (m, 1H), 2.05-1.96 (m, 2H), 1.93-1.71 (m,12H), 0.95-0.88 (m, 2H), 0.65-0.60 (m, 2H); MS (ES+) m/z 434.1, 435.1(M+1).

Example 57 Synthesis of(4-((adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-threonineStep 1. Preparation of tert-butyl(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-threoninate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with tert-butyl L-threoninatehydrochloride. The reaction was stirred at ambient temperature for 16hours. The reaction was concentrated, diluted with ethyl acetate (20 mL)and washed with 5% hydrochloric acid solution (2×10 mL). The aqueouslayer was separated and extracted with ethyl acetate (2×20 mL). Thecombined organics were washed with brine (10 mL), dried over anhydroussodium sulfate and concentrated to yield tert-butyl(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-threoninate(0.23 g). The residue was used in the next step without any furtherpurification: MS (ES+) m/z 502.3, 503.3 (M+1).

Step 2. Preparation of(4-((adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-threonine

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace tert-butyl(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinatewith tert-butyl(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-threoninateand following the residue was purified by reverse-phase HPLC, the titlecompound was as a colorless solid (0.068 g, 34%): ¹H NMR (300 MHz,CDCl₃) δ 7.57 (d, J=8.9 Hz, 1H), 7.55-7.49 (m, 1H), 6.55 (d, J=14.3 Hz,1H), 4.76-4.50 (m, 2H), 3.54 (s, 2H), 2.12-1.96 (m, 4H), 1.85-1.58 (m,12H), 1.36-1.16 (m, 4H), 0.97-0.80 (m, 2H), 0.72-0.58 (m, 2H); MS (ES+)m/z 446.2, 447.2 (M+1).

Example 58 Synthesis of(5-cyclopropyl-2-fluoro-4-((6-methylspiro[2,5]octan-6-yl)-methoxy)benzoyl)-L-prolineStep 1. Preparation methyl(5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]-octan-6-yl)methoxy)benzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations to replace4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl L-prolinate hydrochloride, the title compound was obtained as acolorless gum (0.120 g, 58%): MS (ES+) m/z 444.2, 445.2 (M 1+1).

Step 2. Preparation of(5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoyl)-L-proline

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropanecarboxylatewith methyl(5-cyclopropyl-2-fluoro-4-((6-methylspiro[2.5]octan-6-yl)methoxy)benzoyl)-L-prolinateand following the residue was purified by reverse-phase HPLC, the titlecompound was obtained as a colorless solid (0.066 g, 57%): ¹H NMR (300MHz, CDCl₃) δ 6.98 (d, J=7.1 Hz, 1H), 6.56 (d, J=11.8 Hz, 1H), 4.86-4.60(m, 1H), 3.71 (s, 2H), 3.57-3.45 (m, 2H), 2.41-2.16 (m, 2H), 2.10-1.83(m, 3H), 1.71-1.41 (m, 6H), 1.12 (s, 3H), 1.12-1.08 (m 2H), 0.95-0.84(m, 2H), 0.62-0.56 (m, 2H), 0.32-0.18 (m, 4H); MS (ES+) m/z 430.1, 431.1(M+1).

Example 59 Synthesis of(2S,4R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxypyrrolidine-2-carboxylicacid Step 1. Preparation of(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid

To a solution of (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (2.54 g,19.37 mmol) in 1N aqueous sodium hydroxide (20 mL, 20.0 mmol) and1,4-dioxane (20 mL) was added di-tert-butyl dicarbonate (4.89 mL, 21.31mmol) was added dropwise at 0° C. The resulting solution was slowlywarmed to ambient temperature for 16 h. The reaction mixture wasconcentrated, acidified with 5% aqueous hydrochloric acid and dilutedwith ethyl acetate (50 mL). The aqueous layer was separated andextracted with ethyl acetate (3×50 mL). The combined organic layers werewashed with brine (30 mL), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to afford the title compound (4.38 g) whichwas used without further purification: MS (ES−) m/z 230.3.

Step 2. Preparation of 1-(tert-butyl) 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate

To a solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(1.84 g, 7.96 mmol) in anhydrous acetonitrile (140 mL) was added silver(1) oxide (9.22 g, 39.8 mmol) followed by iodomethane (4.96 mL, 79.6mmol) cooled at 0° C. The resulting suspension was slowly warmed toambient temperature and stirred vigorously for 2 days. The solidmaterial was removed by suction filtration and the filtrate wasconcentrated in vacuo. The residue was purified by flash chromatographyeluting with gradient 0% to 40% of ethyl acetate in hexane to afford thetitle compound as a colorless liquid (1.71 g, 83%): MS (ES+) m/z 160.1(M+1).

Step 3. Preparation of methyl (2S,4R)-4-methoxypyrrolidine-2-carboxylatetrifluoroacetic acid salt

To a solution of 1-(tert-butyl) 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate (1.71 g, 6.59 mmol) indichloromethane (55 mL) was added trifluoroacetic acid (55 mL, 724mmol). The reaction mixture was stirred at ambient temperature for 16 h.The reaction was concentrated, diluted with toluene and concentrated invacuo to afford the title compound as a pale yellow gum (1.62 g, 90%)which was used in the next step without any further purification: ¹H NMR(300 MHz, CDCl₃) δ 4.56 (dd, J=7.4, 10.7 Hz, 1H), 4.23-4.15 (m, 1H),3.83 (s, 3H), 3.69-3.54 (m, 2H), 3.32 (s, 3H), 2.58 (dd, J=7.1, 13.7 Hz,1H), 2.23-2.06 (m, 1H); MS (ES+) m, 160.1.

Step 4. Preparation methyl(2S,4R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxypyrrolidine-2-carboxylate

To a solution of methyl (2S,4R)-4-methoxypyrrolidine-2-carboxylatetrifluoroacetic acid salt (0.083 g, 0.30 mmol) and triethylamine (0.134mL, 0.966 mmol) in dichloromethane (1.5 mL) was added4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl chloride (0.10g, 0.28 mmol) at 0° C. The reaction was slowly warmed to ambienttemperature and stirred for 16 hours. The reaction mixture wasconcentrated then diluted with ethyl acetate (20 mL) and washed with 5%hydrochloric acid solution (10 mL). The aqueous layer was separated andextracted with ethyl acetate (2×20 mL). The combined organic layers werewashed with brine (10 mL), dried over anhydrous sodium sulfate andconcentrated in vacuo to afford the title compound (0.15 g, quantitativeyield) which was used without any further purification: MS (ES+) m/z486.2, 487.2 (M+1).

Step 5. Preparation of(2S,4R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxypyrrolidine-2-carboxylicacid

Following the procedure as described in Example 11, Step 2 and makingvariation as required to replace methyl(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-alaninatewith methyl(2S,4R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxypyrrolidine-2-carboxylateand following the residue was purified by reverse-phase HPLC, the titlecompound was obtained as a colorless solid (0.093 g, 66%): ¹H NMR (300MHz, CDCl₃) δ 7.01 (d, J=7.9 Hz, 1H), 6.53 (d, J=12.1 Hz, 1H), 4.84 (t,J=8.1 Hz, 1H), 4.00-3.95 (m, 1H), 4.13-4.10 (m, 1H, rotomer), 3.65-3.55(m, 2H), 3.51 (s, 2H), 3.24 (s, 3H), 2.61-2.51 (m, 1H), 2.40-2.31 (m,1H), 2.09-2.00 (m, 4H), 1.80-1.62 (m, 12H), 0.95-0.88 (m, 2H), 0.66-0.61(m, 2H): ¹⁹F MNR (300 MHz, CDCl₃) δ −112.84; MS (ES+) m/z 472.3, 473.3(M+1).

Example 60 Synthesis of(1R,3S,5R)-2-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid

Following the procedure as described in Example 59, Step 4 and makingvariation as required to replace methyl(2S,4R)-4-methoxypyrrolidine-2-carboxylate trifluoroacetic acid saltwith (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylic acidhydrochloride, the title compound was obtained as a colorless solid(0.168 g, 89%): ¹H NMR (300 MHz, CDCl₃) δ 7.01 (d, J=7.8 Hz, 1H), 6.56(d, J=11.8 Hz, 1H), 4.63 (dd, J=4.4, 9.1 Hz, 1H), 3.52 (s, 2H), 3.21(dt, J=2.4, 6.3 Hz, 1H), 2.85-2.70 (m, 1H), 2.27 (dd, J=9.5, 13.6 Hz,1H), 2.10-2.03 (m, 4H), 1.89-1.62 (m, 13H), 0.98-0.82 (m, 3H), 0.73-0.58(m, 3H); ¹⁹F MNR (300 MHz, CDCl₃) δ −113.25; MS (ES+) m/z 454.2, 455.2(M+1).

Example 61 Synthesis ofracemate-(1R,3S,5R)-2-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid

Following the procedure as described in Example 59, Step 4 and makingvariation as required to replace methyl(2S,4R)-4-methoxypyrrolidine-2-carboxylate trifluoroacetic acid saltwith racemate-(1R,2S,5S)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid andfollowing the residue was purified by flash chromatography eluting withgradient 0% to 60% of ethyl acetate in hexanes with 0.1% formic acid asan additive, the title compound was obtained as a colorless solid (0.060g, 57%): ¹H NMR (300 MHz, CDCl₃) δ 6.90 (d, J=7.8 Hz, 1H), 6.50 (d,J=11.8 Hz, 1H), 4.68 (d, J=5.3 Hz, 1H), 3.64-3.53 (m, 2H), 3.49 (s, 2H),2.10-1.94 (m, 5H), 1.85-1.68 (m, 13H), 0.95-0.73 (m, 4H), 0.67-0.54 (m,2H); MS (ES+) m/z 454.2, 455.2 (M+1).

Example 62 Synthesis of(2S,3R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylicacid Step 1. Preparation of(2S,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid

To a solution of 1-(tert-butyl) 2-methyl(2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (1.81 g, 7.38 mmol) inanhydrous tetrahydrofuran (60 mL) was added triphenylphosphine (2.03 g,7.75 mmol) and para-nitrobenzoic acid (1.30 g, 7.75 mmol) at 0° C. Asolution of di-isopropyl azadicarboxylate (1.55 mL, 7.89 mmol) inanhydrous tetrahydrofuran (6 mL) was added dropwise. The resultingsolution was stirred at 0° C. for 3 hours before being quenched with 1 Naqueous sodium hydroxide (24 mL, 24.0 mmol). The reaction mixture waswarmed to ambient temperature and stirred for 1 hour. The solution waspartially concentrated in vacuo to remove the tetrahydrofuran thendiluted with water (30 mL) and extracted with ethyl acetate (3×30 mL).The aqueous layer acidified with 10% aqueous potassium bisulfate to pH=2and the resulting precipitate was removed by vacuum filtration. Thefiltrate was treated with saturated sodium chloride and extracted with2:1 chloroform/ethanol (4×50 mL). The combined organic layers was driedover anhydrous magnesium sulfate, filtered, and concentrated in vacuo.The residue was purified by column chromatography, eluting with a 0-30%gradient of ethyl acetate in hexanes to afford the title compound ascolorless syrup (1.14 g, 67%) which was used without furtherpurification: MS (ES+) m/z 230.3, 231.3 (M+1).

Step 2. Preparation of 2-benzyl 1-(tert-butyl)(2S,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate

To a solution of(2S,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid(1.14 g, 4.93 mmol) in methanol (23 mL) was added a solution of cesiumcarbonate (0.80 g, 2.46 mmol) in water (14 mL) at 0° C. The resultingsuspension was slowly warmed to ambient temperature over 0.5 h and thenconcentrated in vacuo. The aqueous residue was diluted with N,N-dimethylformamide (41 mL) and the resulting slurry was cooled at 0° C.then added benzyl bromide (0.6 mL, 4.93 mmol). The reaction mixture waswarmed to ambient temperature and stirred for 16 hours. The reactionmixture was filtered and the filtrate was concentrated in vacuo. Theresidue was diluted with ethyl acetate (250 mL) and washed withsaturated aqueous sodium bicarbonate (100 mL) and water (2×75 mL). Theorganic layer was dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by columnchromatography, eluting with a 0-30% gradient of ethyl acetate inhexanes to afford the title compound (0.49 g, 31%): ¹H NMR (300 MHz,CDCl₃) δ 7.40-7.26 (m, 5H), 5.32-5.06 (m, 2H), 4.63-4.53 (m, 1H), 4.35(d, J=6.8 Hz, 1H), 4.44 (d, J=6.8 Hz, 1H, rotomer), 3.71-3.53 (m, 1H),3.50-3.33 (m, 1H), 2.15-1.90 (m, 3H), 1.31 (s, 9H), 1.43 (s, 9H,rotomer); MS (ES+) m % z 222.2 (M+1).

Step 3. Preparation of benzyl(2S,3R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylate

Following the procedure as described in Example 59, Step 3 and Step 4and making variation as required to replace 1-(tert-butyl) 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate 2-benzyl 1-(tert-butyl)(2S,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate, the title compound wasobtained as colorless syrup (0.16 g, 96%) which was used without anyfurther purification: MS (ES+) m/z 548.3, 549.3 (M+1).

Step 4. Preparation of(2S,3R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylicacid

A suspension of benzyl(2S,3R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylate(0.16 g, 0.28 mmol) and 10% Palladium on charcoal (0.038 g, 0.036 mmol)in methanol (4 mL) was evacuated then flushed with hydrogen gas. Thisprocess was repeated three times and then purged the reaction vesselwith hydrogen atmosphere. The reaction mixture was stirred at ambienttemperature for 16 hours. The reaction mixture was filtered through aCelite plug and the filter bed was rinsed with methanol (2×20 mL) andethyl acetate (2×20 mL). The filtrate was concentrated in vacuo and theresidue was purified by reverse-phase HPLC to afford the title compoundas a colorless solid (0.068 g, 53%): ¹H NMR (300 MHz, CDCl₃) δ 7.00 (d,J=7.8 Hz 1H), 6.55 (d, J=12.1 Hz, 1H), 4.79-4.71 (m, 2H), 3.93-3.76 (m,1H), 3.60-3.45 (m, 1H), 3.52 (s, 2H), 2.14-1.85 (m, 5H), 1.85-1.61 (m,12H), 0.99-0.80 (m, 3H), 0.68-0.58 (m, 2H); MS (ES+) m/z 458.2, 459.1(M+1).

Example 63 Synthesis of(2R,3R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of(2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid

To a solution of 1-(tert-butyl) 2-methyl(2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (0.30 g, 1.22 mmol) intetrahydrofuran (12 mL) was added 0.2N aqueous lithium hydroxide (6.12mL, 1.22 mmol). The reaction was stirred at ambient temperature for 3hours. The reaction mixture was diluted with diethyl ether (30 mL) andextracted with 0.2N aqueous lithium hydroxide (3×5 mL). The combinedaqueous layers were acidified with 5% aqueous hydrochloric acid untilpH=2. The acidic aqueous layer was extracted with ethyl acetate (3×30mL). The organic layer was dried over anhydrous sodium sulfate, filteredand concentrated in vacuo to afford the title compound as a gum (0.25 g,88%) which was used in the next step without any further purification:MS (ES+) m/z 230.3 (M+1).

Step 2. Preparation of 2-benzyl 1-(tert-butyl)(2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate

Following the procedure as described in Example 62, Step 2 and makingnon-critical variations to replace(2S,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acidwith (2S,3S)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylicacid, the title compound was obtained as a colorless gum (0.15 g, 44%):¹H NMR (300 MHz, CDCl₃) δ 7.46-7.28 (m, 5H), 5.29-5.04 (m, 2H),4.46-4.42 (m, 1H), 4.21 (s, 1H) [4.34, rotomer], 3.71-3.51 (m, 2H),2.20-1.97 (m, 2H), 1.97-1.82 (m, 1H), 1.32 (s, 9H) [1.46, rotomer]; MS(ES+) m/z 222.1, 322.1.

Step 3. Preparation of 2-benzyl 1-(tert-butyl)(2R,3R)-3-fluoropyrrolidine-1,2-dicarboxylate

To a solution of 2-benzyl 1-(tert-butyl)(2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate (0.15 g, 0.47 mmol) indichloromethane (1.5 mL) at −78° C. was added diethylaminosulfurtrifluoride (0.1 mL, 0.93 mmol). The reaction mixture was stirred at−78° C. for 2 h, then slowly warmed to ambient temperature and continuedstirring for 2 days. The reaction mixture was cooled at 0° C., carefullyquenched with methanol (2 mL) followed by water (30 mL) and the solventwas concentrated in vacuo. The aqueous residue was extracted with ethylacetate (3×50 mL). The combined organics were washed with saturatedaqueous sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography, eluting with a 0-50% gradient of ethyl acetate inhexanes to afford the title compound as a gum (0.06 g, 36%) which wasdirectly used in the next step without any further analyticalcharacterization.

Step 4. Preparation of benzyl(2R,3R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 59, Step 3 and Step 4and making variation as required to replace 1-(tert-butyl) 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate with 2-benzyl1-(tert-butyl) (2R,3R)-3-fluoropyrrolidine-1,2-dicarboxylate, the titlecompound was obtained as colorless syrup (0.041 g, 51%) which was usedwithout any further purification: MS (ES+) m/z 550.3, 551.3 (M+1).

Step 5. Preparation of(2R,3R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 62, Step 4 and makingvariation as required to replace benzyl(2S,3R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylatewith benzyl(2R,3R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-fluoropyrrolidine-2-carboxylateand following reverse-phase HPLC purification of the residue, the titlecompound was obtained as a colorless solid (0.013 g, 38%): ¹H NMR (300MHz, CDCl₃) δ 7.04 (d, J=7.6 Hz, 1H), 6.53 (d, J=12.0 Hz, 1H), 5.64-5.40(m, 1H), 5.03-4.85 (m, 1H), 3.95-3.77 (m, 1H), 3.62-3.43 (m, 1H), 3.51(s, 2H), 2.38-2.17 (m, 1H), 2.13-1.89 (m, 4H), 1.84-1.57 (m, 12H),0.98-0.78 (m, 3H), 0.71-0.54 (m 2H); MS (ES+) m/z 460.1, 461.1 (M+1).

Example 64 Synthesis of(2R,3S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-fluoropyrrolidine-2-carboxylicacid Step 1-3. Preparation of 2-benzyl 1-(tert-butyl)(2R,3S)-3-fluoropyrrolidine-1,2-dicarboxylate

Following the procedure as described in Example 3, Step 3 and makingvariation as required to replace 2-benzyl 1-(tert-butyl)(2S,3S)-3-hydroxypyrrolidine-1,2-dicarboxylate with 2-benzyl1-(tert-butyl) (2S,3R)-3-hydroxypyrrolidine-1,2-dicarboxylate, the titlecompound was obtained as pale yellow oil (0.13 g, 86%) which was useddirectly in the next step without any further analyticalcharacterization.

Step 2. Preparation of benzyl(2R,3S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 59, Step 3 and Step 4and making variation as required to replace 1-(tert-butyl) 2-methyl(2S,4R)-4-methoxypyrrolidine-1,2-dicarboxylate with 2-benzyl1-(tert-butyl) (2R,3S)-3-fluoropyrrolidine-1,2-dicarboxylate, the titlecompound was obtained as colorless gum (0.12 g, 74%) which was used inthe next step without any further analytical characterization: MS (ES+)m/z 550.3, 551.3 (M+1).

Step 3. Preparation of(2R,3S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 62, Step 4 and makingvariation as required to replace benzyl(2S,3R)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylatewith benzyl(2R,3S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-fluoropyrrolidine-2-carboxylateand following reverse-phase HPLC of the residue, the title compound wasobtained as a colorless solid (0.049 g, 50%): ¹H NMR (300 MHz, CDCl₃) δ6.97 (d, J=7.8 Hz, 1H), 6.55 (d, J=12.0 Hz, 1H), 5.70-5.48 (m, 1H),5.01-4.91 (m, 1H), 3.88-3.71 (m, 1H), 3.64-3.45 (m, 1H), 3.52 (s, 2H),2.33-2.19 (m, 1H), 2.19-1.94 (m, 4H), 1.85-1.60 (m, 12H), 0.99-0.79 (m,3H), 0.69-0.57 (m, 2H); MS (ES+) m/z 460.2, 461.2 (M+1).

Example 65 Synthesis of1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-3-carboxylicacid Step 1. Preparation of methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-3-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with methylpyrrolidine-3-carboxylate hydrochloride, the title compound was obtainedas a colorless oil (0.26 g, 78%): MS (ES+) m/z 456.3 (M+1).

Step 2. Preparation of1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-pyrrolidine-3-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-cyclopropane-1-carboxylatewith methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-3-carboxylate,the title compound was obtained as a colorless solid (0.15 g, 62%): ¹HNMR (300 MHz, CDCl₃) δ 6.98-6.92 (m, 1H), 6.54-6.46 (m, 1H), 3.97-3.57(m, 4H), 3.55-3.39 (m, 3H), 3.25-3.03 (m, 1H), 2.34-2.11 (m, 2H),2.11-1.95 (m, 4H), 1.83-1.63 (m, 11H), 0.94-0.83 (m, 2H), 0.67-0.56 (m,2H), MS (ES−) m/z 440.3 (M−1).

Example 66 Synthesis of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-methylbutanoicacid Step 1. Preparation of tert-butyl(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-valinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with tert-butyl L-valinatehydrochloride, the title compound was obtained as a colorless oil (0.30g, 82%): ¹H NMR (300 MHz, CDCl₃) δ 7.59 (m, 1H), 7.16 (m, 1H), 6.53 (m,1H), 4.68 (m, 1H), 3.53 (s, 2H), 2.25 (m, 1H), 2.04 (m, 4H), 1.74 (m,12H), 1.48 (s, 9H), 0.94 (m, 8H), 0.67 (m, 2H),

Step 2. Preparation of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-methylbutanoicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-valinate,the title compound was obtained as a colorless solid (0.033 g, 37%): ¹HNMR (300 MHz, CDCl₁) δ 7.64-7.56 (m, 1H), 7.17-7.06 (m, 1H), 6.58-6.49(m, 1H), 4.79-4.65 (m, 1H), 3.53 (s, 2H), 2.45-2.27 (m, 1H), 2.14-1.97(m, 4H), 1.87-1.61 (m, 12H), 1.13-0.98 (m, 6H), 0.95-0.83 (m, 2H),0.75-0.57 (m, 2H); MS (ES+) m/z 444.1 (M+1).

Example 67 Synthesis ofN-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-N-methyl-L-valineStep 1. Preparation of tert-butylN-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-N-methyl-L-valinate

Following the procedure as described in Example 7, Step 1 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropane-1-carboxylatewith tert-butyl(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-valinate,the title compound was obtained as a colorless oil (0.31 g, 89%):MS(ES+) m/z 514.4 (M+1).

Step 2. Preparation ofN-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-N-methyl-L-valine

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butylN-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-N-methyl-L-valinate,the title compound was obtained as a colorless solid (0.04 g, 13%): ¹HNMR (300 MHz, CDCl₃) δ 7.05-6.79 (m, 1H), 6.58-6.47 (m, 1H), 4.24-4.05(m, 1H), 3.58-3.45 (m, 2H), 3.13-2.95 (m, 3H), 2.66-2.46 (m, 1H),2.12-1.95 (m, 4H), 1.87-1.64 (m, 12H), 1.16-0.98 (m, 5H), 0.96-0.84 (m,3H), 0.70-0.54 (m, 2H); MS (ES+) m/z 458.2 (M+1).

Example 68 Synthesis of(S)-1-(5-cyclopropyl-4-((4,4-dimethylcyclohexyl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of tert-butyl(5-cyclopropyl-4-((4,4-dimethylcyclohexyl)-methoxy)-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((4,4-dimethylcyclohexyl)methoxy)-2-fluorobenzoic acid,the title compound was obtained as a colorless solid (0.16 g, 78%): MS(ES+) m/z 474.2 (M+1).

Step 2. Preparation of(S)-1-(5-cyclopropyl-4-((4,4-dimethylcyclohexyl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(5-cyclopropyl-4-((4,4-dimethylcyclohexyl)methoxy)-2-fluorobenzoyl)-L-prolinate,the title compound was obtained as a colorless solid (0.12 g, 85%): ¹HNMR (300 MHz, CDCl₃) δ 6.97-6.90 (m, 1H), 6.57-6.48 (m, 1H), 4.77-4.70(m, 1H), 3.83-3.77 (m, 2H), 3.55-3.38 (m, 2H), 2.57-2.45 (m, 1H),2.19-1.84 (m, 4H), 1.81-1.63 (m, 3H), 1.47-1.17 (m, 6H), 0.96-0.83 (m,8H), 0.65-0.57 (m, 2H); MS (ES+) m/z 418.1 (M+1).

Example 69 Synthesis of(4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolineStep 1. Preparation of methyl(4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example, step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid,and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride with methylL-prolinate hydrochloride, the title compound was obtained as acolorless oil (0.23 g, 80%): MS (ES+) m/z 416.2 (M+1).

Step 2. Preparation of(4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-proline

Following the procedure as described in Example 6, step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropane-1-carboxylatewith methyl(4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinate,the title compound was obtained as a colorless solid (0.19 g, 87%): ¹HNMR (300 MHz, CDCl₃) δ 6.98-6.93 (m 1H), 6.50-6.43 (m, 1H), 4.77-4.70 (m1H), 3.83-3.74 (m, 1H), 3.65-3.58 (m, 1H), 3.57-3.37 (m, 2H), 2.56-2.43(m, 1H), 2.23-1.76 (m, 7H), 1.72-1.59 (m, 1H), 1.43-1.18 (m 5H),1.05-0.86 (m, 3H), 0.70-0.61 (m, 3H), 0.42-0.34 (m, 1H); MS (ES+) m/z402.2 (M+1).

Example 70 Synthesis of(S)-1-(4-(adamantan-2-yloxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of tert-butyl(4-(adamantan-2-yloxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-2-yloxy)-5-cyclopropyl-2-fluorobenzoic acid, the titlecompound was obtained as a colorless oil (0.31 g, 84%): MS (ES+) m/z484.3 (M+1).

Step 2. Preparation of(S)-1-(4-(adamantan-2-yloxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(4-(adamantan-2-yloxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinate, thetitle compound was obtained as a colorless solid (0.21 g, 77%): ¹H NMR(300 MHz, CDCl₃) δ 7.00-6.94 (m, 1H), 6.57-6.49 (m, 1H), 4.79-4.69 (m,1H), 4.48-4.38 (m, 1H), 3.61-3.37 (m, 2H), 2.58-2.44 (m, 1H), 2.24-1.71(m, 17H), 1.65-1.50 (m, 2H), 1.00-0.83 (m, 2H), 0.68-0.56 (m, 2H); MS(ES+) m/z 428.2 (M+1).

Example 71 Synthesis of(4-(adamantan-1-ylmethoxy)-2,5-difluorobenzoyl)-L-proline Step 1.Preparation of tert-butyl(4-(adamantan-1-ylmethoxy)-2,5-difluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(adamantan-1-ylmethoxy)-2,5-difluorobenzoic acid, the title compoundwas obtained as a colorless oil (0.10 g, 95%); MS (ES+) m/z 476.3 (M+1).

Step 2. Preparation of(4-(adamantan-1-ylmethoxy)-2,5-difluorobenzoyl)-L-proline

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(4-(adamantan-1-ylmethoxy)-2,5-difluorobenzoyl)-L-prolinate, the titlecompound was obtained as a colorless solid (0.08 g, 89%): ¹H NMR (300MHz, CDCl₃) δ 7.23-7.15 (m, 1H), 6.74-6.65 (m, 1H), 4.78-4.67 (m, 1H),3.58-3.45 (m, 4H), 2.49-2.35 (m, 1H), 2.30-2.14 (m, 1H), 2.10-1.98 (m,4H), 1.98-1.86 (m, 1H), 1.84-1.60 (m, 13H); MS (ES+) m/z 420.2 (M+1).

Example 72 Synthesis of4-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)morpholine-3-carboxylicacid Step 1. Preparation of methyl4-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)morpholine-3-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with methylmorpholine-3-carboxylate hydrochloride, the title compound was obtainedas a colorless oil (0.29 g, 84%); MS (ES+) m/z 472.2 (M+1).

Step 2. Preparation of4-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)morpholine-3-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropane-1-carboxylatewith methyl4-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)morpholine-3-carboxylate,the title compound was obtained as a colorless solid (0.08 g, 28%): ¹HNMR (300 MHz, CDCl₃) δ 7.00-6.88 (m, 1H), 6.55-6.47 (m, 1H), 5.30-5.16(m, 1H), 4.60-4.32 (m, 2H), 4.25-3.96 (m, 1H), 3.89-3.48 (m, 5H),3.45-3.33 (m, 1H), 2.11-1.97 (m, 4H), 1.85-1.62 (m, 11H), 0.96-0.83 (m,2H), 0.71-0.55 (m, 2H); MS (ES+) m/z 458.1 (M+1).

Example 73a and Example 73b Synthesis of(5-cyclopropyl-4-(((S)-1-((R)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)methoxy)-2-fluorobenzoyl)-L-prolineand(5-cyclopropyl-4-(((S)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)methoxy)-2-fluorobenzoyl)-L-prolineStep 1. Preparation of tert-butyl(5-cyclopropyl-4-(((3S)-1-(1-(3,5-dichlorophenyl)ethyl)-piperidin-3-yl)methoxy)-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-(((3S)-1-(1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.32 g,68%): MS (ES+) m/z 563.2, 565.2 (M−56).

Step 2. Preparation of(5-cyclopropyl-4-(((S)-1-((R)-1-(3,5-dichlorophenyl)ethyl)-piperidin-3-yl)methoxy)-2-fluorobenzoyl)-L-prolineand(5-cyclopropyl-4-(((S)-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)methoxy)-2-fluorobenzoyl)-L-proline

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(5-cyclopropyl-4-(((3)-1-(1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)methoxy)-2-fluorobenzoyl)-L-prolinate,following the residue was purified by preparative HPLC (gradient ofacetonitrile in water) to afford the first eluent (stereochemistry atthe methyl substituted benzylic position was arbitrary assigned), thetitle compound as a colorless solid (0.10 g, 34%): ¹H NMR (300 MHz,CDCl₃) δ 7.33-7.16 (m, 3H), 6.97-6.86 (m, 1H), 6.48-6.36 (m, 1H),4.74-4.22 (m, 1H), 3.94-3.61 (m, 4H), 3.58-3.29 (m, 3H), 3.24-3.00 (m,2H), 2.40-1.88 (m, 6H), 1.86-1.65 (m, 4H), 1.52-1.33 (m, 3H), 0.81-0.59(m, 2H), 0.56-0.40 (m, 2H); MS (ES+) m/z 563.4, 565.2 (M+1); and thesecond eluent of the title compound as a colorless solid (0.05 g, 18%):¹H NMR (300 MHz, CDCl₃) δ 7.33-7.16 (m, 3H), 6.96-6.87 (m, 1H),6.50-6.41 (m, 1H), 4.71-4.24 (m, 1H), 3.93-3.55 (m, 3H), 3.50-3.26 (m,1H), 3.20-3.06 (m, 1H), 2.96-2.57 (m, 5H), 2.45-1.93 (m, 5H), 1.91-1.63(m, 4H), 1.52-1.29 (m, 3H), 0.84-0.68 (m, 2H), 0.60-0.43 (m, 2H); MS(ES+) m/z 563.3, 565.1 (M+1).

Example 74 Synthesis of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-2-cyclopropylaceticacid Step 1. Preparation of methyl(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-2-cyclopropylacetate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with methyl(S)-2-amino-2-cyclopropylacetate, the title compound was obtained as acolorless oil (0.20 g, 76%): MS (ES+) m/z 456.3 (M+1).

Step 2. Preparation of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-2-cyclopropylaceticacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropane-1-carboxylatewith methyl(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-2-cyclopropylacetate,the title compound was obtained as a colorless solid (0.123 g, 63%): ¹HNMR (300 MHz, CDCl₃) δ 7.62-7.54 (m, 1H), 7.24-7.12 (m, 1H), 6.59-6.48(m, 1H), 4.13-4.03 (m, 1H), 3.53 (s, 2H), 2.11-1.98 (m, 4H), 1.85-1.63(m, 12H), 1.35-1.22 (m, 1H), 0.96-0.85 (m, 2H), 0.76-0.56 (m, 5H),0.53-0.43 (m, 1H); MS (ES+) m/z 442.3 (M+1).

Example 75 Synthesis of(2S,3S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,3S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with methyl(2S,3S)-3-hydroxypyrrolidine-2-carboxylate hydrochloride, the titlecompound was obtained as a colorless oil (0.46 g, 70%); MS (ES+) m/z472.2 (M+1).

Step 2. Preparation of(2S,3S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropane-1-carboxylatewith methyl(2S,3S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.119 g, 77%): ¹HNMR (300 MHz, CDCl₃) δ 6.98 (m, 1H), 6.54 (m, 1H), 4.69 (m, 2H), 3.73(m, 1H), 3.52 (m, 2H), 3.22 (m, 5H), 2.18 (m, 1H), 2.00 (m, 4H), 1.72(n, 10H),0.90 (m, 2H), 0.62 (m, 2H); MS (ES+) m/z 458.2 (M+1).

Example 76 Synthesis of(2S,3S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-methoxypyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,3S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-methoxypyrrolidine-2-carboxylate

To a stirred solution of methyl(2S,3S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-hydroxypyrrolidine-2-carboxylate(0.20 g, 0.42 mmol) in N,N-dimethylformamide (5 mL) was addediodomethane (0.13 mL, 2.10 mmol), followed by silver oxide (0.29 g, 1.26mmol). The reaction mixture was stirred at ambient temperature for 16 h.diluted with ethyl acetate (50 mL), and filtered through a pad ofCelite. The filtrate was washed with brine (20 mL), saturated aqueoussodium bicarbonate solution (20 mL), dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography eluting with a gradient of ethyl acetate inhexanes (0 to 50%) to give the title compound as a colorless oil (0.125g, 61%): MS (ES+) m/z 486.3 (M+1).

Step 2. Preparation of(2S,3S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-methoxypyrrolidine-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropane-1-carboxylatewith methyl(2S,3S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-methoxypyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.049 g, 42%): ¹HNMR (300 MHz, CDCl₃) δ 7.04-6.86 (m, 1H), 6.57-6.37 (m, 1H), 4.80-4.60(m, 1H), 4.37-4.12 (m, 1H), 3.62-3.15 (m, 6H), 3.16-2.44 (m, 4H),2.31-1.52 (m, 15H), 0.97-0.74 (m, 2H), 0.70-0.48 (m, 2H); MS (ES+) m/z472.2 (M+1).

Example 77 Synthesis of3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)oxetane-3-carboxylicacid Step 1. Preparation of methyl3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)oxetane-3-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with methyl3-aminooxetane-3-carboxylate, the title compound was obtained as acolorless solid (0.34 g, 94%): MS (ES+) m/z 458.2 (M+1).

Step 2. Preparation of3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)oxetane-3-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropane-1-carboxylatewith methyl3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-oxetane-3-carboxylate,the title compound was obtained as a colorless solid (0.030 g, 9%): ¹HNMR (300 MHz, CDCl₃) δ 7.63-7.46 (m, 3H), 6.60-6.51 (m, 1H), 5.21-5.10(m, 2H), 4.84-4.75 (m, 2H), 3.59-3.49 (m, 2H), 2.11-1.95 (m, 4H),1.86-1.61 (m, 12H), 0.98-0.83 (m, 2H), 0.72-0.59 (m, 2H); MS (ES+) m/z444.2 (M+1).

Example 78 Synthesis of3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)thiazolidine-2-carboxylicacid Step 1. Preparation of methyl3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)thiazolidine-2-carboxylate

Following the procedure as described in Example, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with methylthiazolidine-2-carboxylate hydrochloride, the title compound wasobtained as a colorless solid (0.20 g, 49%): MS (ES+) m/z 474.3 (M+1).

Step 2. Preparation of3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)thiazolidine-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropane-1-carboxylatewith methyl3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-thiazolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.14 g, 69%): ¹HNMR (300 MHz, CDCl₃) δ 13.06 (s, 1H), 6.99-6.65 (m, 2H), 5.49-4.96 (m,1H), 4.26-3.64 (m, 2H), 3.61 (s, 2H), 3.20-3.02 (m, 2H), 2.10-1.94 (m,4H), 1.79-1.59 (m, 12H), 0.96-0.83 (m, 2H), 0.68-0.54 (m, 2H); MS (ES+)m/z 460.2 (M+1).

Example 79a and Example 79b Synthesis of(2S)-1-[5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl]pyrrolidine-2-carboxylicacid and(2S)-1-[5-cyclopropyl-4-[[1-[(1R)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl]pyrrolidine-2-carboxylicacid

The compound was synthesized as described in Example 39. The enantiomerwas separated by chiral SFC from mixture of diastereomers using ChiralHPLC conditions as described in Example 113. The first eluting fractionof the title compound was arbitrarily assigned: ¹H NMR (400 MHz,DMSO-d₆) δ 7.47 (t, J=1.9 Hz, 1H), 7.36 (d, J=1.9 Hz, 2H), 6.93-6.65 (m,2H), 4.34 (dd, J=8.6, 4.5 Hz, 1H), 3.87 (dd, J=12.4, 5.8 Hz, 2H),3.61-3.49 (m, 2H), 2.86 (dd, J=59.2, 11.0 Hz, 2H), 2.24 (ddd, J=8.5,6.7, 4.9 Hz, 1H), 2.07-1.66 (m, 9H), 1.42-1.22 (m, 5H), 0.91-0.82 (m,2H), 0.58 (qd, J=5.8, 2.6 Hz, 2H); MS (ES+) m/z 563.2 (M) and the secondeluent of the title compound was arbitrarily assigned: ¹H NMR (400 MHz,DMSO-d₆) δ 7.47 (t, J=1.9 Hz, 1H), 7.36 (d, J=1.9 Hz, 2H), 6.95-6.63 (m,2H), 4.39-4.27 (m, 1H), 3.87 (dd, J=12.2, 5.9 Hz, 2H), 3.54 (dd, J=15.7,7.4 Hz, 2H), 2.93 (d, J=11.0 Hz, 1H), 2.79 (d, J=11.0 Hz, 1H), 2.30-2.16(m, 1H), 2.06-1.65 (m, 9H), 1.30 (t, J=7.3 Hz, 5H), 1.04 (d, J=6.1 Hz,2H), 0.94-0.78 (m, 2H), 0.65-0.51 (m, 2H); MS (ES+) m/z 563.2 (M).

Example 80 Synthesis of(S)-1-(4-(((1R,3S,5R,7R)-5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid (Arbitrarily Assigned) Step 1. Preparation of (S)-tert-butyl(4-(((1R,3S,5R,7R)-5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(((1R,3S,5S,7S)-5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (inquantative yield): MS (ES+) m/z 518.1, 520.1 (M+1).

Step 2. Preparationof(S)-1-(4-(((1R,3S,5R,7R)-5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid (Arbitrarily Assigned)

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl(4-(((1R,3S,5R,7R)-5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)prolinate,the title compound was obtained as a colorless solid (0.07 g, 19%): ¹HNMR (300 MHz, CDCl₃) δ 6.99-6.97 (m, 0.85H), 6.88-6.85 (m, 0.15H), 6.63(br, 1H), 6.53-6.47 (m, 1H), 4.70 (m, 1H), 4.47 (s, 1H), 3.79 (t, J=6.7Hz, 0.2H), 3.51 (t, J=6.4 Hz, 1.8H), 2.36-1.86 (m, 16H), 1.54 (d, J=12.3Hz, 2H), 0.92-0.85 (m, 2H), 0.65-0.62 (m, 2H): MS (ES+) m/z 462.0, 464.0(M+1).

Example 81 Synthesisof(S)-1-(5-chloro-4-(((1R,3S,5R,7R)-5-chloroadamantan-2-yl)oxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid (Arbitrarily Assigned)

Following the procedure as described in Example, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-pyrrolidine-2-carboxylatewith (S)-tert-butyl(5-chloro-4-(((1R,3S,5R,7R)-5-chloroadamantan-2-yl)oxy)-2-fluorobenzoyl)-prolinate,the title compound was obtained as a colorless solid (0.01 g, 19%): ¹HNMR (300 MHz, CDCl₃) δ 7.50-7.48 (m, 0.85H), 7.40-7.38 (m, 0.15H), 6.67,6.60 (m, 1H), 4.70 (br, 1H), 4.50 (br, 1H), 4.49 (s, 1H), 3.81-3.74 (m,0.3H), 3.52 (t, J=6.3 Hz, 1.7H), 2.34-1.88 (m, 15H), 1.52 (d, J=12.0 Hz,2H); MS (ES+) m/z 456.0, 458.0 (M+1).

Example 82 Synthesis of(S)-1-(4-(((1R,3S,5R,7R)-5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid (Arbitrarily Assigned) Step 1. Preparation of tert-butyl(4-(((1R,2S,3S,5R,7R)-5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(((1R,2S,3S,5S,7S)-5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.23 g,64%): MS (ES+) m/z 518.1, 520.1 (M+1).

Step 2. Preparation of (S)-1-(4-(((IR,2S,3S,5R,7R)-5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid (Arbitrarily Assigned)

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(4-(((1R,2S,3S,5R,7R)-5-chloroadamantan-2-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinate,the title compound was obtained as a colorless solid (0.09 g, 45%): ¹HNMR (300 MHz, CDCl₃) δ 7.00 (d, J=7.9 Hz, 0.85H), 6.87 (d, J=7.9 Hz,0.15H), 6.78 (br, 1H), 6.53-6.46 (m, 1H), 4.73-4.68 (m, 1H), 4.33-4.32(m, 1H), 3.80-3.75 (m, 0.2H), 3.52-3.47 (m, 1.8H), 2.57-2.53 (m, 2H),2.43-1.85 (m, 14H), 1.75-1.71 (m 2H), 0.97-0.91 (m, 2H), 0.66-0.61 (m,2H); MS (ES+) m/z 462.1, 464.1 (M+1).

Example 83 Synthesis of(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)piperidine-2-carboxylicacid Step 1. Preparation of methyl(S)-1-(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)piperidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with methyl(S)-piperidine-2-carboxylate, the title compound was obtained as acolorless oil (0.22 g, 67%): MS (ES+) m/z 470.2 (M+1).

Step 2. Preparation of(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)piperidine-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropanecarboxylatewith methyl(S)-1-(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)piperidine-2-carboxylateand following the residue by column chromatography eluting with 10%ethyl acetate in hexanes, the title compound was obtained as a colorlesssolid (0.15 g, 68%): ¹H NMR (300 MHz, CDCl₃) δ 7.59 (br, 1H), 6.95-6.87(m, 1H), 6.53-6.48 (m, 1H), 5.48 (br, 0.75H), 4.66-4.62 (m, 0.25H), 4.39(br, 0.25H), 3.57-3.48 (m, 2.75H), 3.25-2.88 (m, 1H), 2.37-2.17 (m, 1H),2.06-2.02 (m, 4H), 1.79-1.47 (m, 17H), 0.92-0.86 (m, 2H), 0.66-0.58 (m,2H); MS (ES+) m/z 456.1 (M+1).

Example 84 Synthesis of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)succinicacid Step 1. Preparation of di-tert-butyl(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-aspartate

Following the procedure as described in Example, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with di-tert-butyl L-aspartate,the title compound was obtained as a colorless solid (0.24 g, 95%): ¹HNMR (300 MHz, CDCl₃) δ 7.63-7.53 (m, 2H), 6.49 (d, J=14.0 Hz, 1H),4.89-4.83 (m, 1H), 3.49 (s, 2H), 2.94 (dd, J=4.2 Hz, 16.9 Hz, 1H), 2.81(dd, J=4.6 Hz, 16.9 Hz, 1H), 2.08-1.98 (m, 4H), 1.75-1.65 (m, 12H), 1.44(s, 9H), 1.40 (s, 9H), 0.89-0.83 (m, 2H), 0.66-0.61 (m, 2H);

Step 2. Preparation of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)succinicacid

Following the procedure as described in Example, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith di-tert-butyl(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-aspartate,the title compound was obtained as a colorless solid (0.18 g, 92%): ¹HNMR (300 MHz, CDCl₃) δ 8.62 (br, 2H), 7.80-7.73 (m, 1H), 7.54 (d, J=9.0Hz, 1H), 6.49 (d, J=14.2 Hz, 1H), 5.12-5.10 (m, 1H), 3.50 (s, 2H),3.22-3.00 (m, 2H), 2.02 (br, 4H), 1.79-1.67 (m, 12H), 0.92-0.86 (m, 2H),0.67-0.62 (m, 2H); MS (ES+) m/z 460.1 (M+1).

Example 85 Synthesis of(S)-1-(4-(adamantan-1-ylmethoxy)-3-(trifluoromethyl)benzoyl)-pyrrolidine-2-carboxylicacid Step 1. Preparation of tert-butyl(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-3-(trifluoromethyl)benzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-adamantan-1-yl)methoxy)-3-(trifluoromethyl)benzoic acid, the titlecompound was obtained as a colorless solid (0.18 g, 81%): MS (ES+) m/z508.1 (M+1).

Step 2. Preparation of(S)-1-(4-(adamantan-1-ylmethoxy)-3-(trifluoromethyl)benzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cycloproropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-3-(trifluoromethyl)benzoyl)-L-prolinate,the title compound was obtained as a colorless solid (0.09 g, 53%): ¹HNMR (300 MHz, CDCl₃) δ 9.93 (br, 1H), 7.83 (s, 1H), 7.76 (d, J=8.6 Hz,1H), 6.99 (d, J=8.7 Hz, 1H), 4.76-4.71 (m, 1H), 3.66-3.60 (m, 4H),2.38-2.20 (m, 2H), 2.11-1.89 (m, 5H), 1.79-1.66 (m, 12H); MS (ES+) m/z452.1 (M+1).

Example 86 Synthesis of(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)azetidine-2-carboxylicacid Step 1. Preparation of methyl(S)-1-(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)azetidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to (S)-tert-butyl pyrrolidine-2-carboxylatehydrochloride with methyl (S)-azetidine-2-carboxylate hydrochloride, thetitle compound was obtained as a colorless solid (0.16 g, 84%): MS (ES+)m/z 442.1 (M+1).

Step 2. Preparation of(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)azetidine-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzaamido)cyclopropanecarboxylatewith methyl(S)-1-(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)azetidine-2-carboxylate,the title compound was obtained as colorless solid (0.12 g, 78%): ¹H NMR(300 MHz, CDCl₃) δ 8.92 (br, 1H), 7.08 (d, J=7.9 Hz, 1H), 6.53 (d,J=12.5 Hz, 1H), 5.20-5.15 (m, 1H), 4.23-4.08 (m, 2H), 3.52 (s, 2H),2.80-2.68 (m, 1H), 2.60-2.48 (m, 1H), 2.03-1.99 (m, 4H), 1.80-1.68 (m,12H), 0.96-0.89 (m, 2H), 0.65-0.60 (m, 2H); MS (ES+) m/z 428.1 (M+1).

Example 87 Synthesis of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)butanoicacid Step 1. Preparation of tert-butyl(S)-2-(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzamido)butano

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with tert-butyl(S)-2-aminobutanoate hydrochloride, the title compound was obtained as acolorless oil (0.21 g, 95%): MS (ES+) m/z 486.2 (M+1).

Step 2. Preparation of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)butanoicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(S)-2-(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzamido)butanoate,the title compound was obtained as a colorless solid (0.17 g, 96%): ¹HNMR (300 MHz, CDCl₃) δ 8.28 (br, 1H), 7.57 (d, J=9.1 Hz, 1H), 7.22-7.15(m, 1H), 6.53 (d, J=14.3 Hz, 1H), 4.78-4.72 (m, 1H), 3.53 (s, 2H),2.12-2.04 (m, 5H), 1.96-1.84 (m, 1H), 1.80-1.69 (m, 12H), 1.02 (t, J=7.4Hz, 3H), 0.94-0.87 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 430.1 (M+1).

Example 88 Synthesis of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-4-methylpentanoicacid Step 1. Preparation of tert-butyl(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-leucinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with tert-butyl(S)-2-aminobutanoate hydrochloride, the title compound was obtained as acolorless oil (0.19 g, 95%): ¹H NMR (300 MHz, CDCl₃) δ 7.57 (d, J=9.1Hz, 1H), 7.08-7.00 (m, 1H), 6.48 (d, J=14.3 Hz, 1H), 4.73-4.66 (m, 1H),3.49 (s, 2H), 2.04-1.99 (m, 4H), 1.76-1.65 (m, 15H), 1.44 (s, 9H),0.95-0.83 (m, 8H), 0.66-0.61 (m, 2H),

Step 2. Preparation of(S)-2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-4-methylpentanoicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-leucinate,the title compound was obtained as a colorless solid (0.16 g, 95%): ¹HNMR (300 MHz, CDCl₃) δ 7.59 (d, J=9.1 Hz, 1H), 7.04-6.96 (m, 1H), 6.82(br, 1H), 6.53 (d, J=14.3 Hz, 1H), 4.79-4.73 (m, 1H), 3.53 (s, 2H),2.07-2.00 (m, 4H), 1.85-1.69 (m, 15H), 1.00-0.87 (m, 8H), 0.69-0.64 (m,2H): MS (ES+) m/z 458.1 (M+1).

Example 89 Synthesis of(S)-1-(4-(adamantan-1-ylmethoxy)-5-ethyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of tert-butyl(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-ethyl-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-(((3r,5r,7r)-adamantan-1-yl)methoxy)-5-ethyl-2-fluorobenzoic acid, thetitle compound was obtained as a colorless oil (0.23 g, in quantitativeyield): ¹H NMR (300 MHz, CDCl₃) δ 7.15-7.03 (m, 1H), 6.47-6.40 (m, 1H),4.45-4.17 (m, 1H), 3.74-3.31 (m, 4H), 2.58-2.48 (m, 2H), 2.25-2.14 (m,1H), 2.00-1.89 (m, 5H), 1.72-1.60 (m, 13H), 1.42 (s, 9H), 1.21-1.16 (m,3H),

Step 2. Preparation of(S)-1-(4-(adamantan-1-ylmethoxy)-5-ethyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-ethyl-2-fluorobenzoyl)-L-prolinate,the title compound was obtained as a colorless solid (0.13 g, 67%): ¹HNMR (300 MHz, CDCl₃) δ 9.05 (br s, 1H), 7.22 (d, J=8.0 Hz, 1H), 6.53 (d,J=12.1 Hz, 1H), 4.74-4.69 (m, 1H), 3.54-3.47 (m, 2H), 3.47 (s, 2H), 2.61(q, J=7.5 Hz, 2H), 2.41-2.16 (m, 2H), 2.04-1.97 (m, 4H), 1.96-1.85 (m,1H), 1.79-1.66 (m, 12H), 1.19 (t, J=7.5 Hz, 3H): MS (ES+) m/z 430.1(M+1).

Example 90 Synthesis of (S)-1-(5-cyclopropyl-4-(((S,2S,55)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of tert-butyl(5-cyclopropyl-4-(((1S,2S,5S)-6,6-dimethylbicyclo-[3.1.1]heptan-2-yl)methoxy)-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-(((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless oil (0.13 g, 51%):¹H NMR (300 MHz, CDCl₃) δ 6.89-6.79 (m, 1H), 6.50-6.43 (m, 1H),4.46-4.16 (m, 1H), 3.75-3.31 (m, 4H), 2.53-2.43 (m, 1H), 2.28-2.17 (m,1H), 2.10-1.65 (m, 10H), 1.44-1.19 (m, 14H), 0.84-0.77 (m, 5H),0.59-0.51 (m, 2H),

Step 2. Preparationof(S)-1-(5-cyclopropyl-4-(((1S,2S,5S)-6,6-dimethylbicyclo-[3.1.1]heptan-2-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(5-cyclopropyl-4-(((1S,2S,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)methoxy)-2-fluorobenzoyl)-L-prolinate,the title compound was obtained as a colorless solid (0.08 g, 81%): ¹HNMR (300 MHz, CDCl₃) δ 7.40 (br s, 1H), 6.94 (d, J=6.5 Hz, 1H), 6.54 (d,J=12.0 Hz, 1H), 4.74-4.70 (m, 1H), 3.82-3.73 (m, 2H), 3.56-3.41 (m, 2H),2.58-2.40 (m, 2H), 2.25-1.71 (m, 10H), 1.52-1.41 (m, 2H), 1.24 (s, 3H),0.91-0.89 (m, 5H), 0.63-0.62 (m, 2H): MS (ES+) m/z 430.1 (M+1).

Example 91 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,4R)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoicacid, and replace (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloridewith methyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate, the titlecompound was obtained as brown oil (0.25 g, in quantitative yield): MS(ES+) m/z 595.2, 597.2 (M+1).

Step 2. Preparation of(2S,4R)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzaamido)cyclopropanecarboxylatewith methyl(2S,4R)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.05 g, 23%): ¹HNMR (300 MHz, CDCl₃) δ 7.26 (br s, 1H), 7.38-7.33 (m, 3H), 6.90-6.87 (m,1H), 6.35-6.29 (m 1H), 5.28 (brs, 0.5H), 0.51 (brs, 0.5H), 4.76-4.70 (m,1H), 4.32-4.11 (m, 1H), 3.89-3.30 (m, 6H), 2.76-2.62 (m, 1H), 2.42-2.24(m 3H), 1.91-1.64 (m, 9H), 0.80-0.78 (m 2H), 0.56-0.47 (m, 2H); MS (ES+)m/z 581.1, 583.0 (M+1).

Example 92 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,4R)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoicacid, and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate, the title compound wasobtained as a brown oil (0.74 g, 40%): MS (ES+) m/z 649.1, 651.1 (M+1).

Step 2. Preparation of(2S,4R)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzaamido)cyclopropanecarboxylatewith methyl(2S,4R)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.48 g, 82%): ¹HNMR (300 MHz, CDCl₃) δ 7.38-7.37 (m, 1H), 7.32 (br, 2H), 7.01 (d, J=7.8Hz, 1H), 6.52 (d, J=11.9 Hz, 1H), 6.23 (br, 1H), 5.29 (br, 0.5H), 5.12(br, 0.5H), 4.93 (t, J=8.7 Hz, 1H), 4.08 (q, J=8.5 Hz, 1H), 3.86-3.70(m, 4H), 3.02-2.96 (m, 2H), 2.67-2.31 (m, 4H), 2.05-1.95 (m, 1H),1.87-1.83 (m, 3H), 1.53-1.41 (m, 2H), 0.93-0.88 (m, 2H), 0.64-0.60 (m,2H); MS (ES+) m z 635.1, 637.1 (M+1).

Example 93 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)-pyridin-2-yl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,4R)-1-(5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoicacid, and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate, the title compound wasobtained which was used directly without further purification: MS (ES+)m/z 622.3 (M+1).

Step 2. Preparation of(2S,4R)-1-(5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)-pyridin-2-yl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzaamido)-cyclopropanecarboxylatewith methyl(2S,4R)-1-(5-cyclopropyl-4-((1-((6-cyclopropyl-4-(trifluoromethyl)pyridin-2-yl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.03 g, 23% oversteps): ¹H NMR (300 MHz, CDCl₃) δ 7.47-7.46 (m, 1H), 7.38 (s, 1H), 6.95(d, J=7.8 Hz, 1H), 6.46 (d, J=11.6 Hz, 1H), 5.28 (brs, 0.5H), 0.51 (brs,0.5H), 4.77-4.71 (m, 1H), 4.35 (s, 2H), 3.87-3.56 (m, 6H), 2.98-2.92 (m,2H), 2.74-2.55 (m, 2H), 2.36-1.86 (m, 8H), 1.10-1.04 (m, 4H), 0.86-0.83(m, 2H), 0.56-0.53 (m, 2H); MS (ES+) m/z 608.2 (M+1).

Example 94 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)ethoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,4R)-1-(5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)-piperidin-4-yl)ethoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)ethoxy)-2-fluorobenzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate, the title compound wasobtained as a brown oil (0.20 g, 92%): MS (ES+) m/z 595.3, 597.1 (M+1).

Step 2. Preparation of(2S,4R)-1-(5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)ethoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzaamido)cyclopropanecarboxylatewith methyl(2S,4R)-1-(5-cyclopropyl-4-(2-(1-(3,5-dichlorobenzyl)piperidin-4-yl)ethoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.07 g, 27%): ¹HNMR (300 MHz, CDCl₃) δ 7.36-7.29 (m, 3H), 7.05 (br, 1H), 6.96-6.87 (m,1H), 6.47-6.42 (m, 1H), 5.40-5.11 (m, 1H), 4.80-4.51 (m, 1H), 4.26-3.57(m, 6H), 3.37-3.22 (m, 2H), 2.77-2.63 (m, 1H), 2.40-2.22 (m, 3H),1.97-1.90 (m, 1H), 1.78-1.64 (m, 7H), 0.85-0.82 (m, 2H), 0.63-0.55 (m,2H); MS(ES+) m/z 581.1, 583.1 (M+1).

Example 95 Synthesis of(S)-1-(((S)-1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of tert-butyl(4-(((S)-1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with(S)-4-((1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as colorless oil (0.40 g, 83%): MS(ES+) m/z 575.3, 577.2 (M+1).

Step 2. Preparation of(S)-1-(4-(((S)-1-(2-chloro-4-fluorobenzyl)piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(4-(((S)-1-(2-chloro-4-fluorobenzyl)-piperidin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinate,the title compound was obtained as a colorless solid (0.31 g, 86%): ¹HNMR (300 MHz, DMSO-d₆) δ 7.55 (br, 1H), 7.42-7.40 (m, 1H), 7.16-7.15 (m,1H), 6.93-6.87 (m, 1H), 6.80-6.64 (m, 1H), 4.56 (br, 1H), 4.34-4.07 (m,1H), 3.69-3.25 (m, 7H), 2.94-2.57 (m, 3H), 2.26-2.19 (m, 1H), 2.07-2.03(m, 1H), 1.89-1.79 (m, 5H), 1.60 (br, 2H), 0.88-0.85 (m, 2H), 0.60-0.53(m, 2H); MS (ES+) m/z 519.1, 521.1 (M+1).

Example 96 Synthesis of1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylicacid Step 1. Preparation of ethyl1-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylate

To a mixture of ethyl 4,5-dihydro-1H-pyrazole-5-carboxylate (0.77 g, 3.0mmol) and N,N-dimethylpyridin-4-amine (1.22 g, 10.0 mmol) indichloromethane (20 mL) was added a4-(adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl chloride (0.73g, 2.0 mmol) in dichloromethane (10 mL). The mixture was stirred atambient temperature for 24 hours, adjusted pH to ˜4 with hydrochloride 1N solution and then extracted with dichloromethane (2×40 mL), and washedwith 25% ammonium chloride solution and brine; dried over anhydroussodium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography eluting with gradient 10% to 40% of ethyl acetatein hexanes, the title compound was obtained as colorless solid (0.60 g,64%): MS (ES+) m/z 469.2 (M+1).

Step 2. Preparation of1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylicacid

To a mixture of ethyl1-(4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4,5-dihydro-1H-pyrazole-5-carboxylate(0.60 g, 1.28 mmol) in methanol (6 mL) was added a solution of lithiumhydroxide (0.09 g, 3.84 mmol) in water (2 mL). The reaction mixture wasstirred at ambient temperature for 5 hours and concentrated in vacuo.The residue was diluted with ethyl acetate (50 mL), washed withhydrochloride 1 N solution and 25% ammonium chloride solution; driedover anhydrous sodium sulfate and concentrated in vacuo. The residue waspurified by column chromatography eluting with gradient 2%-10%dichloromethane in methanol, the title compound was obtained as acolorless solid (0.23 g, 41%): ¹H NMR (300 MHz, CDCl₃) δ 10.98 (s, 1H),7.09 (d, J=7.6 Hz 1H), 6.98 (br, 1H), 5.08-5.02 (m, 1H), 3.50 (s, 2H),3.39-3.20 (m, 2H), 2.04-1.98 (m, 4H), 1.79-1.67 (m, 12H), 0.91-0.85 (m,2H), 0.65-0.60 (m, 2H); ¹³C-APT NMR (75 MHz, CDCl₃) δ 171.4, 166.2,161.6 (d, J=10.0 Hz), 158.6 (d, J=251 Hz), 148.0, 127.9 (d, J=2.9 Hz),126.9 (d, J=4.3 Hz), 112.6 (d, J=14.7 Hz), 98.7 (d, J=25.9 Hz), 78.4,56.9, 39.4, 37.8, 36.9, 33.7, 28.0, 9.5, 6.7; MS (ES+) m/z 441.2 (M+1).

Example 97 Synthesis of5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzoyl)-L-prolinetrifluoroacetic acid salt Step 1. Preparation of tert-butyl(5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzoic acid,the title compound was obtained as a colorless syrup (1.36 g, 96%yield): MS (ES+) m/z 528.9, 527.0 (M+1).

Step 2. Preparation of5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzoyl)-L-prolinetrifluoroacetic acid salt

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzoyl)-L-prolinate,the title compound (0.87 g, 75% yield) was obtained as a colorlesssolid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.05 (br, s, 0.5H), 8.07 (d, J=2.7Hz, 0.7H), 8.01 (d, J=2.7 Hz, 0.3H), 7.98 (d, J=2.7 Hz, 0.7H) 7.93 (d,J=2.7 Hz, 0.3H), 7.60 (d, J=6.8 Hz, 0.7H), 7.57 (d, J=6.8 Hz, 0.3H),7.42 (br, s, 0.5H), 7.09 (d, J=10.5 Hz, 0.7H), 7.07 (d, J=10.4 Hz,0.3H), 4.36-4.31 (m, 0.8H), 4.22-4.18 (m, 0.4H), 4.11-4.64 (m, 2H),3.55-3.50 (m, 0.6H), 3.40-3.30 (m, 2H), 2.30-2.18 (m, 1H), 2.10-1.77 (m,4H), 0.99 (d, J=6.7 Hz, 6H); MS (ES+) m/z 473.0, 471.0 (M+1).

Example 98 Synthesis of(5-cyclopropyl-4-((5-cyclopropyl-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzoyl)-L-prolinetrifluoroacetic acid salt and(4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinetrifluoroacetic acid salt

To a mixture of5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzoyl)-L-proline(0.53 g, 1.12 mmol), cyclopropylboronic acid (0.57 g, 6.75 mmol),potassium phosphate (1.19 g, 5.6 mmol) and tricyclohexylphosphinetetrafluoroborate (0.082 g, 0.224 mmol) in toluene (10 mL) and water (1mL) under a nitrogen atmosphere was added palladium acetate (0.056 g,0.168 mmol). The reaction mixture was heated at 100° C. for 16 h andcooled to ambient temperature. To the reaction mixture was added Water(20 mL) and extracted with ethyl acetate (3×20 mL). The combined organicextracts was washed with brine, dried over anhydrous sodium sulfate andfiltered. The solvent was concentrated in vacuo and the residue waspurified by column chromatography eluting with 5% methanol indichloromethane to afford the first title compound as a colorless solid(0.064 g, 12% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.71 (d, J=2.3 Hz,0.8H), 7.61 (d, J=2.6 Hz, 0.2H), 7.58-7.26 (br, s, 2H), 7.00 (d, J=7.4Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.45 (d, J=10.3 Hz, 0.2H), 6.35 (d,J=10.9 Hz, 0.8H), 4.72-4.59 (m, 1H), 4.08 (d, J=6.6 Hz, 2H), 3.45 (t,J=6.6, 6.6 Hz, 2H), 2.34-1.82 (m, 8H), 1.04 (d, J=6.7 Hz, 6H), 1.00-0.98(m, 4H), 0.72-0.61 (m, 4H); MS (ES+) m/z 484.0, 483.0 (M+1) and secondthe title compound was obtained as a colorless solid (0.29 g, 53%): ¹HNMR (300 MHz, CDCl₃) δ 8.80-8.44 (br, s, 2H), 7.76 (d, J=2.5 Hz, 0.8H),7.70 (d, J=1.8 Hz, 0.2H), 7.55 (d, J=6.7 Hz, 0.8H), 7.51 (d, J=6.7 Hz,0.2H), 7.17 (d, J=2.1 Hz, 0.2H), 6.92 (d, J=2.6 Hz, 0.8H), 6.68 (d,J=9.7 Hz, 0.2H), 6.47 (d, J=10.4 Hz, 0.8H), 4.68 (t, J=6.2 Hz, 1H), 4.18(d, J=6.3 Hz, 0.4H), 4.10 (d, J=6.5 Hz, 1.6H), 3.86-3.74 (m, 0.4H),3.56-3.43 (m, 1.6H), 2.32-2.25 (m, 2H), 2.20-1.88 (m, 4H), 1.05 (d,J=6.7 Hz, 6H), 1.15-0.95 (m, 2H), 0.75-0.70 (m, 0.4H), 0.68-0.63 (m,1.6H), MS (ES+) m/z 479.0, 477.0 (M+1).

Example 99 Synthesis of 1-(4-((1-(4-chloro-2-(trifluoromethyl)benzyl1)-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt Step 1. Preparation tert-butyl(4-((1-(4-chloro-2-(trifluoromethyl)benzyl)-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((1-(4-chloro-2-(trifluoromethyl)benzyl)-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.14 g,30%): MS (ES+) m/z 631.2, 629.2 (M+1).

Step 2. Preparation of1-(4-((I-(4-chloro-2-(trifluoromethyl)benzyl)-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetic acid salt

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith tert-butyl(4-((1-(4-chloro-2-(trifluoromethyl)benzyl)-3-fluoroazetidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolinate,the title compound was obtained as a colorless solid (0.10 g, 79%): ¹HNMR (300 MHz, CDCl₃) δ 8.96-8.05 (br, s, 2.5H), 7.92 (s, 1H), 7.67-7.60(m, 2H), 6.87 (d, J=7.64 Hz, 1H), 6.44 (d, J=11.23, 1H), 4.88-4.77 (m,4H), 4.58 (dd, J=5.90 Hz, 7.72 Hz, 1H), 4.42-4.32 (m, 4H), 3.76-3.72 (m,0.2H), 3.52-3.43 (m, 1.8H), 2.35-2.26 (m, 2H), 2.00-1.83 (m, 4H), 1.26(t, J=7.14 Hz, 1H), 0.88-0.80 (m, 2H), 0.56-0.50 (m, 2H); MS (ES+) m/z575.0, 573.0 (M+1).

Example 100 Synthesis of(S)-1-(4-((1-(3-Chloro-4-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoylchloride

Following the procedure as described in Example 046, Step 1 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoic acid with(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoicacid, the title compound was obtained as a pale yellow solid that wasused in the next step without purification.

Step 2. Preparation of(S)-1-(4-((1-(3-chloro-4-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 046, Step 2 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with(S)-5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoylchloride and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acidtrifluoroacetic acid salt with (2S,4R)-4-fluoropyrrolidine-2-carboxylicacid hydrochloric acid salt, the title compound was obtained as acolorless solid (0.023 g, 6.2% yield): ¹H NMR (300 MHz, CDCl₃) δ7.37-7.32 (m, 3H), 6.89 (d, J=7.8 Hz, 1H), 6.32 (d, J=11.8 Hz, 1H), 5.28(s, 0.5H), 5.11 (s, 0.5H), 4.74 (t, J=8.2 Hz, 1H), 4.10 (dd, J=13.6, 6.6Hz, 1H), 3.90-3.52 (m, 6.5H), 3.32-3.21 (m, 1.5H), 2.76-2.62 (m, 1H),2.45-2.18 (m, 3H), 1.98-1.78 (m, 4H), 1.73-1.60 (m, 4H), 0.84-0.74 (m,2H), 0.58-0.45 (m, 2H); MS (ES+) m/z 582.0, 581.0 (M+1).

Example 101 Synthesis of(2S,4R)-1-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1 Preparation of4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)-benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride

Following the procedure as described in Example 046, Step 1 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoic acid with4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a pale yellow solid that wasused in the next step without purification.

Step 2. Preparation of(2S,4R)-1-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 046, Step 2 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acidtrifluoroacetic acid salt with (2S,4R)-4-fluoropyrrolidine-2-carboxylicacid hydrochloric acid salt, the title compound was obtained as acolorless solid (0.010 g, 3.3% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.06(s, 1H)), 7.70 (d, J=4.5 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.34 (d,J=11.7 Hz, 1H), 5.26 (s, 0.5H), 5.08 (s, 0.5H), 4.74 (t, J=8.6 Hz, 1H),4.31-3.52 (m, 9H), 2.75-1.63 (m, 9H), 0.86-0.79 (m, 2H), 0.56-0.47 (m,2H): Note: Acidic proton not observed: MS (ES+) m/z 621.2, 619.2 (M+1).

Example 102 Synthesis of(2S,4R)-1-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride

Following the procedure as described in Example 046, Step 1 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoic acid with4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a pale yellow solid that wasused in the next step without purification.

Step 2. Preparation of(2S,4R)-1-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 046, Step 2 and makingnon-critical variations as required to replace4-(I-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with with4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acidtrifluoroacetic acid salt with (2S,4R)-4-fluoropyrrolidine-2-carboxylicacid hydrochloric acid salt, the title compound was obtained as acolorless solid (0.010 g, 2.7%): ¹H NMR (300 MHz, CDCl₃) δ 8.16 (s,1H)), 7.77 (d, J=5.2 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 6.30 (d, J=11.3Hz, 1H), 5.27 (s, 0.5H), 5.10 (s, 0.5H), 4.69 (t, J=8.7 Hz, 1H),4.37-3.37 (m, 8H), 3.04-2.12 (m, 9H), 0.89-0.83 (m, 2H), 0.57-0.44 (m,2H); Note: Acidic proton not observed; MS (ES+) m/z 639.2, 637.2 (M+1).

Example 103 Synthesis of(2S,4R)-1-(5-cyclopropyl-2-fluoro-4-((1-(2-fluoro-5-(trifluoromethyl)benzyl)-piperidin-4-yl)methoxy)benzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation methyl(2S,4R)-1-(5-cyclopropyl-2-fluoro-4-((1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)benzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-2-fluoro-4-((1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)benzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate hydrochloric acid salt,the title compound was obtained as a colorless solid (0.30 g, 90%yield): MS (ES+) m/z 599.2 (M+1).

Step 2. Preparation(2S,4R)-1-(5-cyclopropyl-2-fluoro-4-((1-(2-fluoro-5-(trifluoromethyl)benzyl)-piperidin-4-yl)methoxy)benzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(ter-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(2S,4R)-1-(5-cyclopropyl-2-fluoro-4-((1-(2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)benzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.07 g, 23%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.14 (d, 0.1=5.2 Hz, 1H), 7.67-7.62(m, 1H), 7.22 (t, J=8.9 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.34 (d, J=11.8Hz, 1H), 5.25 (s, 0.5H), 5.08 (s, 0.5H), 4.72 (t, J=8.5 Hz, 1H),4.40-4.03 (m, 2H), 3.80-3.49 (m, 7H), 2.74-2.48 (m, 3H), 2.03-1.67 (m,6H), 0.85-0.76 (m, 2H), 0.57-0.46 (m, 2H); Note: Acidic proton notobserved; MS (ES+) m/z 585.3 (M+1).

Example 104 Synthesis of(2S,4R)-1-(4-((1-(4-chloro-3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation methyl(2S,4R)-1-(4-((1-(4-chloro-3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((1-(4-chloro-3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate hydrochloric acid salt,the title compound was obtained as a colorless solid (0.28 g, 91%yield): MS (ES+) m/z 567.1, 565.1 (M+1).

Step 2. Preparation(2S,4R)-1-(4-((1-(4-chloro-3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(2S,4R)-1-(4-((1-(4-chloro-3-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.04 g, 13%): ¹HNMR (300 MHz, CDCl₃) δ 7.59 (d, J 6.6 Hz, 1H), 7.40-7.34 (m, 1H), 7.14(t, J=8.6 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 6.32 (d, J=11.7 Hz, 1H), 5.28(s, 0.5H), 5.10 (s, 0.5H), 4.72 (t, J=8.6 Hz, 1H), 4.51-4.34 (m, 1H),3.89-3.67 (m, 3H), 3.62-3.10 (m, 2H), 2.78-2.17 (m, 4H), 2.02-1.59 (m,6H), 0.83-0.76 (m, 2H), 0.57-0.45 (m, 2H); Note: Acidic proton notobserved; MS (ES+) m/z 553.2, 551.2 (M+1).

Example 105 Synthesis of(2S,4R)-1-(4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation methyl(2S,4R)-1-(4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate hydrochloric acid salt,the title compound was obtained as a colorless solid (0.37 g, 95%): MS(ES+) m/z 633.2, 631.2 (M+1).

Step 2. Preparation(2S,4R)-1-(4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(2S,4R)-1-(4-((1-(3-chloro-5-(trifluoromethoxy)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.10 g, 27%): ¹HNMR (300 MHz, CDCl₃) δ 8.20 (br, s, 0.5H), 7.41 (s, 1H), 7.26 (m, 1H),7.20 (m, 1H), 6.83 (d, J=7.8 Hz, 1H), 6.30-6.24 (m, 1H), 5.23 (s, 0.5H),5.05 (s, 0.5H), 4.66 (t, J=8.6 Hz, 1H), 4.28-4.23 (m 1H), 3.87-3.46 (m,6H), 3.34-3.23 (m, 1H), 2.71-2.46 (m, 3H), 2.34-2.07 (m, 1H), 1.99-1.54(m, 6H), 0.79-0.68 (m, 2H), 0.52-0.36 (m, 2H); MS (ES+) m/z 619.3, 617.3(M+1).

Example 106 Synthesis of(2S,4R)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation methyl(2S,4R)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate hydrochloric acid salt,the title compound was obtained as a colorless solid (0.53 g, 50%): MS(ES+) m/z 635.0, 633.0 (M+1).

Step 2. Preparation(2S,4R)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(ter-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(2S,4R)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.21 g, 42%): ¹HNMR (300 MHz, CDCl₃) δ 8.24 (s, 1H), 7.60-7.54 (m, 2H), 6.82 (d, J=7.7Hz, 1H), 6.24 (d, J=11.5 Hz, 1H), 5.26 (s, 0.5H), 5.08 (s, 0.5H), 4.65(t, J=8.7 Hz, 1H), 4.46-4.36 (m, 1H), 4.31-4.22 (m, 1H), 4.09 (dd,J=25.5, 10.5 Hz, 1H), 3.90-3.44 (m, 4H), 3.32-3.21 (m, 1H), 3.07-2.90(m, 2H), 2.75-2.39 (m, 2H), 2.34-2.04 (m, 4H), 1.94-1.81 (m, 1H),0.87-0.76 (m, 2H), 0.54-0.39 (m, 2H); Note: Acidic proton not observed;MS (ES+) m/z 621.2, 619.2 (M+1).

Example 107 Synthesis of(2S,4R)-1-(5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(isopropylamino)benzyl)-piperidin-4-yl)methoxy)benzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation methyl(2S,4R)-1-(5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(isopropylamino)benzyl)piperidin-4-yl)methoxy)benzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(isopropylamino)benzyl)piperidin-4-yl)methoxy)benzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate hydrochloric acid salt,the title compound was obtained as a colorless solid (0.19 g, 36%): MS(ES+) m/z 588.3 (M+1).

Step 2. Preparation(2S,4R)-1-(5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(isopropylamino)benzyl)piperidin-4-yl)methoxy)benzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(2S,4R)-1-(5-cyclopropyl-2-fluoro-4-((1-(5-fluoro-2-(isopropylamino)benzyl)piperidin-4-yl)methoxy)benzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.03 g, 18%): ¹HNMR (300 MHz, CDCl₃) δ 6.97-6.88 (m, 2H), 6.84-6.76 (m, 1H), 6.65-6.55(m, 1H), 6.34 (d, J=11.8 Hz, 1H), 5.84 (br. s, 1H), 5.26 (s, 0.5H), 5.08(s, 0.5H), 4.82-4.70 (m, 1H), 4.14-4.00 (m, 1H), 3.88-3.49 (m, 6H),3.46-3.18 (m, 2H), 2.76-2.55 (m, 1H), 2.49-2.16 (m, 3H), 2.00-1.51 (m,6H), 1.29-1.09 (m, 7H), 0.87-0.69 (m, 2H), 0.59-0.42 (m, 2H); MS (ES+)m/z 574.3 (M+1).

Example 108 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-(2,4-dichloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation methyl(2S,4R)-1-(5-cyclopropyl-4-((1-(2,4-dichloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((1-(2,4-dichloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S,4R)-4-fluoro-pyrrolidine-2-carboxylate hydrochloric acidsalt, the title compound was obtained as a colorless solid (0.03 g,18%): MS (ES+) m/z 601.1, 599.1 (M+1).

Step 2. Preparation(2S,4R)-1-(5-cyclopropyl-4-((1-(2,4-dichloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(2S,4R)-1-(5-cyclopropyl-4-((1-(2,4-dichloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as colorless solid (0.040 g, 19%): ¹HNMR (300 MHz, CDCl₃) δ 7.63-7.45 (m, 1H), 7.41 (d, J=6.6 Hz, 1H),6.70-6.89 (m, 1H), 6.42 (d, J=11.4 Hz, 1H), 5.18 (s, 0.5H), 5.01 (s,0.5H), 4.69 (s, 2H), 3.94-3.63 (m, 5H), 3.60-3.43 (m, 1H), 3.22-2.95 (m,2H), 2.64-2.15 (m, 3H), 2.03-1.77 (m, 4H), 1.68-1.44 (m, 2H), 1.42-1.33(s, 1H), 0.89-0.73 (m, 2H), 0.66-0.49 (m, 2H): MS (ES+) m/z 587.2, 585.2(M+1).

Example 109 Synthesis of(2S,4R)-1-(4-((1-((5-chloro-6-isopropoxypyridin-3-yl)methyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation methyl(2S,4R)-1-(4-((1-((5-chloro-6-isopropoxypyridin-3-yl)methyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((1-((5-chloro-6-isopropoxypyridin-3-yl)methyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S,4R)-4-fluoropyrrolidine-2-carboxylate hydrochloric acid salt,the title compound was obtained as a colorless solid (0.38 g, 98%): MS(ES+) m/z 626.2, 624.2 (M+1).

Step 2. Preparation(2S,4R)-1-(4-((1-((5-chloro-6-isopropoxypyridin-3-yl)methyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(2S,4R)-1-(4-((1-((5-chloro-6-isopropoxypyridin-3-yl)methyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.15 g, 41%): ¹HNMR (300 MHz, DMSO-d₆) δ 7.89 (s, 1H), 7.86 (s, 1H), 6.82 (d, J=7.3 Hz,1H), 6.21 (d, J=11.3 Hz, 1H), 5.43-5.19 (m, 3H), 4.63 (t, J=7.2 Hz, 1H),4.26-3.93 (m, 2H), 3.88-3.58 (m, 4H), 3.49 (m, 2H), 3.25-3.04 (m, 1H),2.89-2.58 (m, 3H), 2.23-1.9 (m 4H), 1.92-1.76 (m, 1H), 1.39 (d, J=6.2Hz, 6H), 0.93-0.70 (m, 2H), 0.60-0.33 (m, 2H); MS (ES+) min 612.2, 610.2(M+1).

Example 110 Synthesis of2-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzamido)-2-cyclobutylaceticacid

To a stirred solution of4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropropyl-2-fluorobenzoicacid (0.25 g, 0.50 mmol) in tetrahydrofuran (10 mL) was added2-amino-2-cyclobutylacetic acid (0.128 g, 1.0 mmol)1,1′-carbonyldiimidazole (CDI) (0.097 g, 0.60 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.379 g, 2.50 mmol). Thereaction mixture was stirred at ambient temperature for 16 h thendiluted with dichloromethane (50 mL), washed with saturated ammoniumchloride solution, brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by reverse phasepreparative HPLC (gradient of acetonitrile in water) to afford the titlecompound as a colorless solid (0.054 g, 18%): ¹H NMR (300 MHz, CDCl₃) δ9.36-8.59 (br, s, 1H), 8.02 (s, 1H), 7.60-7.43 (m, 3H), 7.12 (dd,J=12.1, 7.5 Hz, 1H), 6.38 (d, J=13.5 Hz, 1H), 4.56 (t, J=7.0 Hz, 1H),4.24-4.07 (m, 2H), 4.06-3.84 (m, 2H), 3.19 (t, J=12.8 Hz, 2H), 2.93-2.67(m, 3H), 2.29-2.14 (m, 2H), 2.14-1.70 (m, 9H), 0.94-0.79 (m, 2H),0.70-0.54 (m, 2H): MS (ES+) m/z 617.2, 615.2 (M+1).

Example 111 Synthesis of(2S,3R,4R)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of 1-(tert-butyl) 2-methyl(2S)-3-methyl-4-oxopyrrolidine-1,2-dicarboxylate

To a solution of 1-(tert-butyl) 2-methyl(S,Z)-3-((dimethylamino)methylene)-4-oxopyrrolidine-1,2-dicarboxylate(12.0 g, 40.3 mmol) in anhydrous acetone (250 mL) under nitrogen, wasadded palladium on carbon (2.40 g). This reaction mixture was purgedwith hydrogen and stirring was continued under one atmosphere hydrogengas for two days. This mixture was filtered through a pad of Celite andwashed with acetone. The filtrate was concentrated in vacuo. The residuewas purified by column chromatography (50% ethyl acetate in hexane) toafford the title compound as a light yellow syrup (7.00 g, 67%): ¹H NMR(300 MHz, CDCl₃) δ 4.74 (dd, J=23.2, 9.8 Hz, 0.5H), 4.24-4.07 (m, 0.5H),3.93-3.78 (m, 2H), 3.67 (d, J=3.7 Hz, 3H), 2.91-2.75 (m, 0.5H),2.64-2.49 (m, 0.5H), 1.38 (d, J=6.6 Hz, 9H), 1.24 (d, J=7.4 Hz, 1.5H),0.99 (d, J=7.2 Hz, 1.5H),

Step 2, Preparation of methyl(2S)-3-methyl-4-oxopyrrolidine-2-carboxylate trifluoroacetate

To a stirred solution of 1-(tert-butyl) 2-methyl(2S)-3-methyl-4-oxopyrrolidine-1,2-dicarboxylate (2.50 g, 9.72 mmol) indichloromethane (15 mL) was added trifluoroacetic acid (1.50 mL, 19.5mmol). This reaction mixture was stirred at ambient temperature for 6 h.The crude product was concentrated in vacuo to afford the title compound(2.80 g, quantitative yield) as dark brown syrup that was used in nextstep without any purification.

Step 3. Preparation of methyl(2S)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-methyl-4-oxopyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations as required to replace4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withmethyl (2S)-3-methyl-4-oxopyrrolidine-2-carboxylate trifluoroacetic acidsalt, the title compound was obtained as a colorless solid (1.60 g,91%): MS (ES+) m/z 644.2, 642.2 (M+1).

Step 4. Preparation of methyl(25)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate

To a stirred solution of methyl(2S)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-methyl-4-oxopyrrolidine-2-carboxylate(0.50 g, 0.78 mmol) in tetrahydrofuran (10 mL),(S)-(−)-2-methyl-CBS-oxazaborolidine solution (0.8 mL, 0.78 mmol) in asingle portion. This mixture was cooled to −78° C. then boranedimethylsulfide (74 μL, 0.78 mmol) was added over 5 minutes. Thereaction mixture was stirred at −78° C. for 20 minutes then placed in awater bath at ambient temperature and continued stirring at ambienttemperature for 7 minutes. The reaction was quenched by dropwiseaddition of methanol (5 mL) and continued stirring for 2.5 hours. Thesolvent concentrated in vacuo. The residue was dissolved in ethylacetate (50 mL) and washed with 0.2 M hydrochloride acid solution (50mL×2). The organic layer was dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyeluting with 3% methanol in dichloromethane to afford the title compoundas a colorless solid (0.23 g, 45%): MS (ES+) m/z 647.3, 645.3 (M+1).

Step 5. Preparation of methyl(2S)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylate

To a stirred solution of methyl(2S)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate(0.45 g, 0.70 mmol) in dichloromethane (7 mL), a solution ofdiethylaminosulfur trifluoride (369 μL, 2.80 mmol) and hydrogen fluoridepyridine (72 μL, 2.80 mmol) in dichloromethane (2.80 mL) dropwise at 0°C. This reaction mixture was warmed to ambient temperature and continuedstirring for 3 hours. The reaction was quenched by the addition ofsaturated sodium bicarbonate solution (50 mL) and extracted with ethylacetate (2×50 mL). The combined organic extracts was washed with brine,dried over anhydrous sodium sulfate and filtered. The solvent wasconcentrated in vacuo and the residue was purified by columnchromatography eluting with 50% ethyl acetate in hexane to afford thetitle compound (0.16 g, 34%) as a colorless solid: MS (ES+) m/z 649.1,647.1 (M+1).

Step 6. Preparation of Synthesis of(2S,3R,4R)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33 (step 2), and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(2S)-1-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylate,the title compound was obtained as colorless solid (0.047 g, 34%): ¹HNMR (300 MHz, DMSO-d₆) δ 8.13 (s, 1H), 7.55 (s, 2H), 6.89-6.72 (m, 2H),6.32-6.15 (m, 2H), 4.89 (d, J=53.3 Hz, 1H), 4.37-4.97 (m, 4H), 3.88-3.39(m, 4H), 3.15-2.76 (m, 2H), 2.72-2.28 (m, 2H), 2.25-1.77 (m, 4H),1.44-1.23 (m, 3H), 0.91-0.70 (m, 2H), 0.56-0.30 (m, 2H): MS (ES+) m/z635.1, 633.1 (M+1).

Example 112 Synthesisof(S)-1-(5-cyclopropyl-4-(1-(3,5-dichlorobenzyl)piperidin-4-yloxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

The title compound was synthesized as described in Example 39: LCMS(ESI) Method A: RT=5.20 min, m/z 535.2 [M+1]; ¹H NMR (400 MHz, DMSO-d₆)δ 7.50 (s, 1H), 7.38 (s, 2H), 7.00-6.90 (m, 1H), 6.81-6.66 (m, 1H),4.61-4.50 (m, 1H), 4.34-4.10 (m, 1H), 3.56-3.51 (m, 3H), 2.65-2.57 (m,2H), 2.39-2.30 (m, 2H), 2.28-2.18 (m, 1H), 2.05-1.65 (m, 9H), 0.88-0.84(m, 2H), 0.59-0.51 (m, 2H),

Example 113 Synthesis of(S)-2-cyclopropyl-2-(5-cyclopropyl-4-((1-((R)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-ylmethoxy)-2-fluorobenzamido)acetic

The title compound was synthesized as described in Example 28. Theenantiomer was separated by chiral SFC from mixture of diastereomers.The second eluting fraction was arbitrarily assigned to as((S)-2-cyclopropyl-2-(5-cyclopropyl-4-((S)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzamido)aceticacid: Chiral HPLC (Cellulose-1, 4.6×250 mm, 5 μm; mobile Phase: A:supercritical CO₂, B: methanol (0.5% DEA), A:B=65:35; flow: 3.0 mL/min;column temperature: 42.6 OC; RT=5.34 min); LCMS (ESI) Method C: RT=6.89min, m/z 611.2 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ 7.99 (br s, 1H),7.48-7.43 (m, 5H), 7.32-7.19 (m, 4H), 7.01-6.99 (m, 1H), 4.56 (s, 1H),4.10-4.08 (m, 2H), 3.89-3.88 (m, 1H), 3.51-3.48 (m, 2H), 3.16-3.14 (m,2H), 2.10-2.05 (m, 1H), 1.34 (s, 3H), 1.23-1.20 (m, 1H), 0.91-0.85 (m,2H), 0.61-0.68 (m, 2H), 0.42-0.32 (m, 4H),

Example 114 Synthesis of(S)-2-cyclopropyl-2-(5-cyclopropyl-4-(1-((S)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzamido)aceticacid

The title compound was synthesized as described in Example 28. Theenantiomer was separated by chiral SFC from mixture of diastereomersusing Chiral HPLC conditions as described in Example 113. The firsteluting fraction was arbitrarily assigned as((S)-2-cyclopropyl-2-(5-cyclopropyl-4-((1-((S)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzamido)aceticacid: LCMS (ESI) Method C: RT=6.89 min, m/z 611.0 [M+1]; ¹H NMR (400MHz, DMSO-d₆) δ 7.92 (br s, 1H), 7.48-7.43 (m, 5H), 7.32-7.19 (m, 4H),7.01-6.98 (m, 1H), 4.55 (s, 1H), 4.12-4.07 (m, 2H), 3.93-3.92 (m, 1H),3.51-3.50 (m, 2H), 3.16-3.14 (m, 2H), 2.10-2.06 (m, 1H), 1.34 (s, 3H),1.23-1.18 (m, 1H), 0.91-0.89 (m, 2H), 0.61-0.60 (m, 2H), 0.44-0.36 (m,4H),

Example 115 Synthesis of(2S,3S)-1-(5-cyclopropyl-4-((1-((R)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)-3-methylpyrrolidine-2-carboxylicacid

The title compound was synthesized as described in Example 28. Theenantiomer was separated by chiral SFC from mixture of diastereomersusing Chiral HPLC conditions as described in Example 113. The secondeluting fraction was arbitrarily assigned as(2S,3S)-1-(5-cyclopropyl-4-((1-((R)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)-3-methylpyrrolidine-2-carboxylicacid: LCMS (ESI) Method C: RT=6.67 min, m/z 625.0 [M+1]: ¹H NMR (400MHz, DMSO-d₆) δ 7.48-7.48 (m, 2H), 7.45-7.40 (m, 3H), 7.32-7.28 (m, 2H),7.23-7.19 (m, 1H), 6.99-6.72 (m, 2H), 4.56 (s, 1H), 4.08-4.04 (m, 2H),3.63-3.49 (m, 2H), 3.15-3.13 (m, 2H), 2.86-2.84 (m, 2H), 2.33-2.25 (m,1H), 2.07-1.97 (m, 2H), 1.55-1.46 (m, 2H), 1.34-1.33 (m, 3H), 1.15-1.14(m, 2H), 1.05-1.03 (m, 1H), 0.89-0.84 (m, 2H), 0.60-0.57 (m, 2H),

Example 116 Synthesis of(2S,3S)-1-(5-cyclopropyl-4-((1-((S)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)-3-methylpyrrolidine-2-carboxylic acid

The title compound was synthesized as described in Example 28. Theenantiomer was separated by chiral SFC from mixture of diastereomersusing Chiral HPLC conditions as described in Example 113. The firsteluting fraction was arbitrarily assigned as(2S,3S)-1-(5-cyclopropyl-4-((1-((S)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)-3-methylpyrrolidine-2-carboxylicacid: LCMS (ESI) Method C: RT=6.67 min, m/z 625.0 [M+1]; ¹H NMR (400MHz, DMSO-d₆) δ 7.45-7.48 (m, 2H), 7.45-7.43 (m, 3H), 7.32-7.28 (m, 2H),7.23-7.19 (m, 1H), 6.98-6.74 (m, 2H), 4.56 (s, 1H), 4.07-4.03 (m, 2H),3.63-3.43 (m, 2H), 3.16-3.13 (m, 2H), 2.86-2.84 (m, 2H), 2.33-2.25 (m,1H), 2.28-2.25 (m, 2H), 1.49-1.45 (m 2H), 1.34-1.33 (m, 3H), 1.15-1.13(m, 2H), 1.03-1.02 (m, 1H), 0.89-0.83 (m, 2H), 0.59-0.55 (m, 2H),

Example 117 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-((S)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

The title compound was synthesized as described in Example 28. Theenantiomer was separated by chiral SFC from mixture of diastereomersusing Chiral HPLC conditions as described in Example 113. The firsteluting fraction was arbitrarily assigned as(2S,4R)-1-(5-cyclopropyl-4-((1-((S)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid: LCMS (ESI) Method A: RT=6.45 min, m/z 629.2 [M+1]; ¹H NMR (400MHz, DMSO-d₆) δ 7.49-7.48 (m, 2H), 7.45-7.43 (m 3H), 7.32-7.28 (m, 2H),7.23-7.21 (m, 1H), 7.00-6.84 (m, 2H), 5.37-5.18 (m, 1H), 4.56 (s, 1H),4.46-4.42 (m, 1H), 4.08-3.88 (m, 3H), 3.64-3.40 (m, 2H), 3.16-3.13 (m,2H), 2.86-2.84 (m, 2H), 2.23-2.08 (m, 2H), 1.34-1.35 (m, 3H), 0.90-0.83(m, 2H), 0.61-0.58 (m, 2H),

Example 118 Synthesis of(S)-2-cyclopropyl-2-(5-cyclopropyl-4-((1-((R)-(3,5-dichlorophenyl)-(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzamido)aceticacid

The title compound was synthesized as described in Example 26. Theenantiomer was arbitrarily assigned as(S)-2-cyclopropyl-2-(5-cyclopropyl-4-((1-((R)-(3,5-dichlorophenyl)-(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzamido)aceticacid: LCMS (ESI) Method A: RT=6.87 min, m/z 625.2 [M+1]: ¹H NMR (400MHz, DMSO-d₆) δ 7.49-7.06 (m, 9H), 6.93-6.86 (m, 1H), 4.44 (s, 1H),3.99-3.94 (m, 2H), 3.81-3.73 (m, 1H), 2.84-2.76 (m, 2H), 2.03-1.95 (m,1H), 1.87-1.76 (m, 4H), 1.48-1.38 (m, 2H), 1.24-1.19 (m, 2H), 0.90-0.82(m, 2H), 0.61-0.58 (m, 2H), 0.52-0.30 (m, 4H),

Example 119 Synthesis of(S)-2-cyclopropyl-2-(5-cyclopropyl-4-((1-((S)-(3,5-dichlorophenyl)-(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzamido)aceticacid

The title compound was synthesized as described in Example 26. Theenantiomer was arbitrarily assigned as(S)-2-cyclopropyl-2-(5-cyclopropyl-4-((1-((S)-(3,5-dichlorophenyl)(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzamido)aceticacid: LCMS (ESI) Method A: RT=6.98 min, m/z 625.2 [M+1]; ¹H NMR (400MHz, DMSO-d₆) δ 7.47-7.20 (m, 9H), 6.93-6.89 (m, 1H), 4.44 (s, 1H),3.95-3.93 (m, 2H), 3.85-3.81 (m, 1H), 2.82-2.71 (m, 2H), 2.03-1.95 (m,1H), 1.89-1.71 (m, 4H), 1.48-1.33 (m, 2H), 1.25-1.13 (m, 2H), 0.91-0.80(m, 2H), 0.61-0.55 (m, 2H), 0.51-0.31 (m, 4H),

Example 120 Synthesis of(R)-2-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzamido)-2-cyclopropylaceticacid

The title compound was synthesized as described in Example 9: LCMS (ESI)Method A: RT=7.78 min, m/z 502.1 [M+1]: ¹H NMR (400 MHz, DMSO-d₆) δ 8.51(br s, 1H), 7.42-7.16 (m, 5H), 5.374 (s, 2H), 3.83-3.79 (m, 1H),2.05-2.01 (m, 1H), 1.23-1.17 (m, 1H), 0.98-0.93 (m, 2H), 0.70-0.66 (m,2H), 0.54-0.36 (m, 4H),

Example 121a and Example 121b Synthesis of(2S,3S)-1-(5-cyclopropyl-4-((1-((R)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-3-methylpyrrolidine-2-carboxylicacid and(2S,3S)-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-3-methylpyrrolidine-2-carboxylicacid

The title compound was synthesized as described in Example 39. Theenantiomer was separated by chiral SFC from mixture of diastereomersusing Chiral HPLC conditions as described in Example 113. The firsteluting fraction was arbitrarily assigned as(2S,3S)-1-(5-cyclopropyl-4-((1-((R)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-3-methylpyrrolidine-2-carboxylicacid: LCMS (ESI) Method A: RT=6.45 min, m/z 631.1 [M+1]; 1H NMR (400MHz, DMSO-d₆) δ 7.71 (s, 1H), 7.45 (s, 2H), 6.87-6.68 (m, 2H), 4.77-4.75(m, 1H), 3.88-3.82 (m, 3H), 3.57-3.41 (m, 2H), 3.00 (s, 2H), 2.32-2.26(m, 2H),2.05-1.94 (m, 3H), 1.79-1.36 (m, 6H), 1.13 (d, J=6.8 Hz, 3H),0.87-0.81 (m 2H), 0.57-0.56 (m, 2H); and the second eluting fraction wasarbitrarily assigned as(2S,3S)-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-3-methylpyrrolidine-2-carboxylicacid: LCMS (ESI) Method A: RT=6.47 min, m/z 631.1 [M+1]; ¹H NMR (400MHz, DMSO-d₆) δ 7.71 (s, 1H), 7.45 (s, 2H), 6.86-6.74 (m, 2H), 4.78-4.75(m, 1H), 3.88-3.83 (m, 3H), 3.57-3.42 (m, 2H), 3.00 (m, 2H), 2.33-2.27(m, 2H), 2.07-1.94 (m, 3H), 1.79-1.36 (m, 6H), 1.13 (d, J=6.8 Hz, 3H),0.87-0.81 (m, 2H), 0.57-0.56 (m, 2H),

Example 122 Synthesis of(5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)azetidin-1-yl)methyl)-2-fluorobenzoyl)-L-prolineStep 1. Preparation of tert-butyl(5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)azetidin-1-yl)methyl)-2-fluorobenzoyl)-L-prolinate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)azetidin-1-yl)methyl)-2-fluorobenzoicacid, the title compound was obtained as a colorless foam (0.24 g, 45%):MS (ES+) m/z 563.0, 564.9 (M+1).

Step 2. Preparation of(5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)azetidin-1-yl)methyl)-2-fluorobenzoyl)-L-proline

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-pyrrolidine-2-carboxylatewith tert-butyl(5-cyclopropyl-4-((3-(3,5-dichlorophenoxy)azetidin-1-yl)methyl)-2-fluorobenzoyl)-L-prolinate,the title compound was obtained as a colorless solid: ¹H NMR (300 MHz,DMSO-d₆) δ 12.67 (br s, 1H), 11.06 (br s, 1H), 7.38-7.26 (m, 1H),7.26-7.21 (m, 1H), 7.03-6.88 (m, 3H), 5.16 (br s, 1H), 4.76-4.54 (m,4H), 4.38-4.15 (m, 3H), 3.56-3.46 (m, 1H), 3.32-3.17 (m, 1H), 2.29-2.13(m, 1H), 2.09-1.98 (m, 1H), 1.94-1.73 (m, 3H), 1.01-0.87 (m, 2H),0.70-0.53 (m, 2H); MS (ES+) m/z 509.1, 507.1 (M+1)

Example 123a and Example 123b Synthesis of(S)-1-(5-cyclopropyl-4-((1-((R)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid and(S)-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)-methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

The title compound was synthesized as described in Example 39. Theenantiomer was separated by chiral SFC from mixture of diastereomersusing Chiral HPLC conditions as described in Example 113. The firsteluting fraction was arbitrarily assigned as(S)-1-(5-cyclopropyl-4-((1-((R)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid: LCMS (ESI) Method A: RT=6.40 min, m/z 617.0 [M+I]; ¹H NMR (400MHz, DMSO-d₆) δ 7.71 (s, 1H), 7.42 (s, 2H), 6.88-6.76 (m, 2H), 4.77-4.75(m, 1H), 4.32 (m, 1H), 3.88-3.83 (m, 2H), 3.51-3.48 (m, 1H), 3.01-2.97(m, 2H), 2.33-2.30 (m, 2H), 2.08-1.97 (m, 3H), 1.89-1.76 (m, 6H),1.37-1.34 (m, 2H), 0.82-0.79 (m, 2H), 0.60-0.51 (m, 2H) and the secondeluting fraction was arbitrarily assigned as(S)-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid: LCMS (ESI) Method A: RT=6.40 min, m/z 617.0 [M+1]; ¹H NMR (400MHz. DMSO-d₆) δ 7.71 (s, 1H), 7.45 (s, 2H), 6.88-6.72 (m, 2H), 4.83-4.71(m, 1H), 4.34-3.83 (m, 3H), 3.51-3.47 (m, 1H), 3.01-2.99 (m, 2H),2.33-1.68 (m, 11H), 1.37-1.35 (m, 2H), 0.87-0.81 (m, 2H), 0.59-0.54 (m,2H),

Example 124 Synthesis of(S)-5-(4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-azaspiro[2.4]heptane-6-carboxylicacid Step 1. Preparation of4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride

To a solution of4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid (1.84 mmol) in anhydrous acetonitrile (12.30 mL) was added oxalylchloride (2.40 mL, 27.6 mmol) and N,N-dimethylformamide (0.020 mL). Thereaction mixture was stirred at ambient temperature for 1.5 h, and thenevaporated to dryness in vacuo. The resulting residue was used withoutfurther purification or characterization.

Step 2. Preparation of(S)-5-(4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-azaspiro[2.4]heptane-6-carboxylicacid

To a solution of4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride (1.84 mmol) in acetonitrile (5.0 mL) was addedN,N-diisopropylethylamine (0.64 mL, 3.68 mmol) followed by(S)-6-carboxy-5-azaspiro[2.4]heptan-5-ium trifluoroacetate (0.21 g, 0.83mmol) dissolved in acetonitrile (1.0 mL). The reaction mixture wasstirred at ambient temperature overnight, and then diluted with aqueoushydrochloric acid (1 mol/L, 10 mL). After extraction with ethyl acetate(3×75 mL), the pooled organic extracts were dried over anhydrousmagnesium sulfate, filtered, and evaporated in vacuo. The residue waspurified by preparatory HPLC (acetonitrile and water with 0.1% formicacid) to obtain(S)-5-(4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-azaspiro[2.4]heptane-6-carboxylicacid as a colorless solid (0.11 g, 21% yield): ¹H NMR (300 MHz, CDCl₃) δ7.84 (d, J=8.1 Hz, 1H), 7.66 (s, 1H), 7.52 (d, J=7.2 Hz, 1H), 6.79 (d,J=7.5 Hz, 1H), 6.25 (d, J=11.4 Hz, 1H), 4.64 (t, J=7.5 Hz, 1H),4.16-3.99 (m, 3H), 3.84-3.75 (m, 1H), 3.54 (d, J=10.2 Hz, 1H), 3.34-3.22(m, 1H), 3.07-2.90 (m, 2H), 2.82-2.65 (m, 2H), 2.24-1.84 (m, 7H), 0.80(d, J=8.4 Hz, 2H), 0.61-0.42 (m, 6H): Note: COOH proton not observed, MS(ES+) m/z 627.1 (M+1).

Example 125 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-((S)-(3,5-dichlorophenyl)(phenyl)methyl)-piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

The title compound was synthesized as described in Example 26. Theenantiomer was separated by chiral SFC from mixture of diastereomers.The first eluting fraction was arbitrarily assigned as(2S,4R)-1-(5-cyclopropyl-4-((1-((S)-(3,5-dichlorophenyl)(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid: Chiral HPLC (column: OJ-H, 4.6×250 mm, 5 μm; mobile Phase: A:supercritical CO₂, B: methanol (0.5% NH₄OH), A: B=70:30: flow: 2.1mL/min; column temperature: 41.4 OC; RT=5.24 min); LCMS (ESI) Method A:RT=6.77 min, m/z 643.2 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ 7.46-7.22 (m,8H), 6.93-6.81 (m, 2H), 5.41-5.18 (m, 1H), 4.47-4.03 (m, 2H), 3.94-3.87(m, 2H), 3.78-3.54 (m, 1H), 3.46-3.41 (m, 2H), 2.82-2.77 (m, 2H),2.23-2.17 (m, 1H), 2.01-1.93 (m, 3H), 1.81-1.72 (m, 3H), 1.48-1.37 (m,2H), 0.89-0.79 (m, 2H), 0.70-0.61 (m, 2H),

Example 126a and Example 126b Synthesis of(2S,4R)-1-(4-((4-cyano-1-((R)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid and(2S,4R)-1-(4-((4-cyano-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

The title compound was synthesized as described in Example 39. Theenantiomer was separated by chiral SFC from mixture of diastereomersusing Chiral HPLC conditions as described in Example 113. The firsteluting fraction was arbitrarily assigned as(2S,4R)-1-(4-((4-cyano-1-((R)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid: LCMS (ESI) Method A: RT=6.00 min, m/z 606.2 [M+1]; ¹H NMR (400MHz, DMSO-d₆) δ 7.49 (s, 1H), 7.40 (s, 2H), 6.96-6.80 (m, 2H), 4.17 (m,4H), 3.64 (m, 4H), 3.04 (m, 2H), 2.16 (m, 7H), 1.27 (m, 5H), 0.75 (m,3H) and the second eluting fraction was arbitrarily assigned as(2S,4R)-1-(4-((4-cyano-1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid: LCMS (ESI) Method A: RT=6.05 min, m/z 606.2 [M+1]; ¹H NMR (400MHz, DMSO-d₆) δ 7.49 (s, 1H), 7.40 (s, 2H), 6.97-6.81 (m, 2H), 4.17 (m,4H), 3.64 (m, 4H), 3.04 (m, 2H), 2.16 (m, 7H), 1.27 (m, 5H), 0.75 (m,3H),

Example 127 Synthesis of(2S,4R)-1-(4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of tert-butyl4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate

Following the procedure as described in Example 128, Step 1 and makingvariation as required to replace 3-chloro-4-fluorobenzyl4-methylbenzenesulfonate with 2-chloro-4-(trifluoromethyl)-benzylmethanesulfonate, the title compound was obtained as yellow oil (2.74 g,54% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.67-7.60 (m, 2H), 7.55-7.45 (m,1H), 7.40 (d, J=8.3 Hz, 1H), 6.50 (d, =12.4 Hz, 1H), 3.99 (d, J=18.0 Hz,2H), 3.68 (s, 2H), 2.85-2.71 (m, 2H), 2.52 (t, J=10.6 Hz, 2H), 2.10-1.90(m, 4H), 1.91-1.75 (m, 1H), 1.55 (s, 9H), 0.95-0.85 (m, 2H), 0.67-0.59(m, 2H); MS (ES+) m/z 559.8, 562.2 (M+1).

Step 3. Preparation of4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropropyl-2-fluorobenzoicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropanecarboxylatewith tert-butyl4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate,the title compound obtained was used without further purification.

Step 4. Preparation of methyl(2S,4R)-1-(4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations to replace4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((1-(3-chloro-4-fluorobenzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropropyl-2-fluorobenzoicacid, the title compound was obtained as yellow oil (0.29 g, 38% yield):1H NMR (300 MHz, CDCl₃) δ 7.70-7.60 (m, 2H), 7.55-7.40 (m, 2H), 7.01 (d,J=7.8 Hz, 1H), 6.52 (d, J=11.7 Hz, 1H), 5.20 (d, J=51.9 Hz, 1H), 4.80(t, J=8.6 Hz, 1H), 3.98 (d, J=18.0 Hz, 2H), 3.75 (s, 3H), 3.72-3.59 (m,4H), 2.82-2.46 (m, 6H), 2.30-2.12 (m, 1H), 2.00-1.69 (m, 3H), 0.90-0.85(m, 2H), 0.64-0.57 (m, 2H); MS (ES+) m/z 633.3, 635.2 (M+1).

Step 5. Preparation of(2S,4R)-1-(4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 230, Step 2 and makingnon-critical variations as required to replace methyl(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylatewith methyl(2S,4R)-1-(4-((1-(2-chloro-4-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.11 g, 39%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.90 (d, J=7.8 Hz, 1H), 7.73 (s, 1H),7.62 (d, J=7.8 Hz, 1H), 6.91 (d, J=7.8 Hz, 1H), 6.40 (d, J=11.4 Hz, 1H),5.19 (d, J=52.2 Hz, 1H), 4.86-4.70 (m, 1H), 4.55 (s, 2H), 4.00 (sextet,J=9.9 Hz, 2H), 3.77-3.65 (m, 5H), 3.20 (t, J=10.2 Hz, 2H), 2.75-2.55 (m,1H), 2.52-2.16 (m, 4H), 1.95-1.80 (m, 1H), 0.84 (d, J=8.4 Hz, 2H), 0.51(s, 2H); Note: acidic proton not observed, MS (ES+) m/z 619.1 (M+1).

Example 128 Synthesis of(2S,4R)-1-(4-((1-(3-chloro-4-fluorobenzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of tert-butyl4-((1-(3-chloro-4-fluorobenzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate

To a solution of 3-chloro-4-fluorobenzyl 4-methylbenzenesulfonate (0.46g, 1.46 mmol) in N,N-dimethylformamide (4.5 mL) was added potassiumcarbonate (0.47 g, 3.37 mmol) and4-((4-carboxy-2-cyclopropyl-5-fluorophenoxy)methyl)-4-fluoropiperidin-1-iumchloride (0.43 g, 1.12 mmol). The reaction mixture was stirred at 70° C.for 2 h then diluted with brine (100 mL) and extracted with ethylacetate (3×80 mL). The combined organic extracts were dried overanhydrous magnesium sulfate and filtered. The filtrate was concentratedin vacuo and the residue was purified by column chromatography to affordthe title compound as a colorless solid (0.35 g, 47% yield): ¹H NMR (300MHz, CDCl₃) δ 7.42-7.34 (m, 2H), 7.21-7.12 (m, 1H), 7.06 (t, J=8.6 Hz,1H), 6.49 (d, J=12.4 Hz, 1H), 3.97 (d, J=18.1 Hz, 2H), 3.47 (s, 2H),2.80-2.65 (m, 2H), 2.37 (t. J=10.7 Hz, 2H), 2.05-1.90 (m, 4H), 1.85-1.72(m, 1H), 1.55 (s, 9H), 0.94-0.82 (m, 2H), 0.68-0.57 (m, 2H); MS (ES+)m/z 554.3, 556.3 (M+45).

Step 2. Preparation of4-((1-(3-chloro-4-fluorobenzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace ethyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)cyclopropanecarboxylatewith tert-butyl4-((1-(3-chloro-4-fluorobenzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate,the title compound obtained was used without further purification.

Step 3. Preparation of methyl(2S,4R)-1-(4-((1-(3-chloro-4-fluorobenzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingnon-critical variations to replace4-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with4-((1-(3-chloro-4-fluorobenzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride with(2S,4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-1-ium chloride, the titlecompound was obtained as yellow oil (0.29 g, 73% yield): ¹H NMR (300MHz, CDCl₃) δ 7.42 (dd, J=7.2, 1.9 Hz, 1H), 7.24-7.17 (m, 1H), 7.13-7.01(m, 2H), 6.55 (d, J=11.7 Hz, 1H), 5.24 (d, J=52.2 Hz, 1H), 4.93-4.77 (m,11H), 4.00 (d, J=18.1 Hz, 2H), 3.80 (m, 3H), 3.79-3.62 (m, 2H), 3.51 (s,2H), 3.47-3.38 (m, 1H), 2.80-2.65 (m, 3H), 2.41 (t, J=10.8 Hz, 2H),2.31-2.15 (m, 1H), 2.08-1.85 (m, 4H), 0.97-0.85 (m, 2H), 0.69-0.60 (m,2H); MS (ES+) m/z 583.2, 585.3 (M+1).

Step 4. Preparation of(2S,4R)-1-(4-((1-(3-chloro-4-fluorobenzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 230, Step 2 and makingnon-critical variations as required to replace methyl(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylatewith methyl(2S,4R)-1-(4-((1-(3-chloro-4-fluorobenzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.044 g, 15%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.52 (d, J=4.8 Hz, 1H), 7.42-7.32 (m,1H), 7.18 (t, J=8.7 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.34 (d, J=11.4 Hz,1H), 5.18 (d, J=51.9 Hz, 1H), 4.72 (t, J=8.7, 1H), 4.22 (q, J=13.2 Hz,2H), 4.10-3.87 (m, 2H), 3.81-3.43 (m, 4H), 3.13-2.85 (m, 2H), 2.76-2.55(m, 1H), 2.50-2.10 (m, 5H), 1.92-1.78 (m, 1H), 0.82 (d, J=8.2 Hz, 2H),0.49 (br s, 2H); Note: acidic proton not observed: MS (ES+) m/z 569.2,571.2 (M+1).

Example 129 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

The compound was synthesized as described in Example 39: LCMS (ESI)Method A: RT=5.96 min, m/z 599.0 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ 7.48(s, 1H), 7.38 (s, 2H), 6.98-9.73 (m, 2H), 5.42-5.20 (m, 1H), 4.50-3.42(m, 6H), 2.78-2.58 (m, 3H), 2.27-1.73 (m, 8H), 1.30 (d, J=6.4 Hz, 3H),0.89-0.87 (m, 2H), 0.64-0.59 (m, 2H),

Example 130 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

The compound was synthesized as described in Example 39: LCMS (ESI)Method C: RT=5.57 min, m/z 611.0 [M+1]: ¹H NMR (400 MHz, DMSO-d₆) δ 7.49(s, 1H), 7.38-7.37 (m, 2H), 6.91-6.71 (m, 2H), 5.42-5.20 (m, 1H),4.50-4.16 (m, 1H), 3.92-3.81 (m, 2H), 3.78-3.62 (m, 4H), 3.51-3.42 (m,2H), 3.21 (s, 3H), 2.98-2.94 (m, 1H), 2.80-2.76 (m, 1H), 2.26-1.90 (m,4H), 1.80-1.64 (m, 3H), 1.40-1.23 (m, 2H), 0.89-0.81 (m, 2H), 0.61-0.52(m, 2H),

Example 131 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-((R)-1-(3,5-dichlorophenyl)-2-methoxyethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

The compound was synthesized as described in Example 39: LCMS (ESI)Method C: RT=5.54 min, m/z 611.0 [M+l]; ¹H NMR (400 MHz, DMSO-d₆) δ 7.49(s, 1H), 7.38-7.37 (m, 2H), 6.91-6.71 (m, 2H), 5.40-5.20 (m, 1H),4.49-4.13 (m, 1H), 3.90-3.81 (m, 2H), 3.78-3.60 (m, 4H), 3.50-3.43 (m,2H), 3.21 (s, 3H), 2.98-2.94 (m, 1H), 2.80-2.76 (m, 1H), 2.24-1.90 (m,4H), 1.80-1.67 (m, 3H), 1.40-1.20 (m, 2H), 0.90-0.81 (m, 2H), 0.61-0.52(m, 2H),

Example 132 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-((R)-1-(3,5-dichlorophenyl)ethyl)-4-methylpiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid and(2S,4R)-1-(5-cyclopropyl-4-((1-((R)-1-(3,5-dichlorophenyl)ethyl)-4-methylpiperidin-4-yl)-methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

The compound was synthesized as described in Example 39. The enantiomerwas separated by chiral SFC from mixture of diastereomers using ChiralHPLC conditions as described in Example 113. The first eluting fractionwas arbitrarily assigned as(2S,4R)-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-methylpiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid: LCMS (ESI) Method C: RT=6.29 min, m/z 595.2 [M+1]; ¹H NMR (400MHz, DMSO-d₆) δ 7.46 (s, 1H), 7.37 (s, 2H), 6.94-6.85 (m, 2H), 5.35-5.22(m, 1H), 4.51-4.46 (m, 1H), 3.80-3.74 (m, 3H), 3.59-3.46 (m, 2H),2.60-2.57 (m, 2H), 2.50-2.25 (m, 4H), 2.01-1.99 (m, 1H), 1.67-1.64 (m,2H), 1.43-1.38 (m, 2H), 1.29-1.27 (m, 3H), 1.08 (s, 3H), 0.90-0.86 (m,2H), 0.62-0.56 (m, 2H) and the second eluting fraction was arbitrarilyassigned as(2S,4R)-1-(5-cyclopropyl-4-((1-((R)-1-(3,5-dichlorophenyl)ethyl)-4-methylpiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid: LCMS (ESI) Method C: RT=6.29 min, m/z 595.1 [M+l]; ¹H NMR (400MHz. DMSO-d₆) δ 7.47 (s, 1H), 7.37 (s, 2H), 6.94-6.85 (m, 2H), 5.35-5.22(m, 1H), 4.51-4.46 (m, 1H), 3.80-3.74 (m, 3H), 3.59-3.46 (m, 2H),2.60-2.57 (m, 2H), 2.46-2.25 (m, 4H), 2.01-1.99 (m, 1H), 1.67-1.63 (m2H), 1.43-1.38 (m, 2H), 1.29-1.26 (m, 3H), 1.02 (s, 3H), 0.90-0.86 (m,2H), 0.62-0.56 (m, 2H),

Example 133 Synthesis of(S)-3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-2-oxooxazolidine-4-carboxylicacid Step 1. Preparation of(S)-3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-2-oxooxazolidine-4-carboxylicacid

To a stirred solution of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.25 g,0.7 mmol) in anhydrous dichloromethane (10 mL) was added anhydrousdimethylformamide (0.1 mL, 1.3 mmol) and oxalyl chloride (0.18 mL, 2.1mmol). The reaction mixture was stirred at ambient temperature for 1 hand concentrated in vacuo to afford crude4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl chloride, whichwas used directly in the subsequent step. To a stirred solution of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl chloride inanhydrous tetrahydrofuran (10 mL) was added(S)-2-oxooxazolidine-4-carboxylic acid (0.11 g, 0.9 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL, 3.6 mmol). The reactionmixture was stirred at ambient temperature for 16 h and ethyl acetate(50 mL) was added. The mixture was washed with hydrochloric acid (1 M,2×40 mL) and brine (40 mL): dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography (0% to 30% ethyl acetate+0.2% formic acid in hexanes) toafford(S)-3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-2-oxooxazolidine-4-carboxylicacid as a colorless solid (0.055 g, 17%): ¹H NMR (300 MHz, DMSO-d₆) δ12.79 (s, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.87 (d, J=13.2 Hz, 1H), 3.63 (s,2H), 3.33 (s, 2H), 2.06-1.99 (m, 4H), 1.75-1.66 (m, 13H), 0.94-0.88 (m,2H), 0.62-0.56 (m, 2H); F NMR (282 MHz, DMSO-(d) δ −109.3 (s, 1F). MS(ES−) m/z 412.3 (M−45).

Example 134 Synthesis of(S)-1-(4-cyclopropyl-5-((3,5-dichlorophenoxy)methyl)thiophene-2-carbonyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of methyl4-bromo-5-methylthiophene-2-carboxylate

To a solution of methyl 5-methylthiophene-2-carboxylate (9.8 g, 62.8mmol) in acetic acid (100 mL) was added ferric chloride (2.0 g, 12.4mmol) and bromine (3.1 mL, 75 mmol) in acetic acid (50 mL) at 0° C. andit was stirred at room temperature for 5 hours. The reaction mixture wasquenched with sodium dithionite (5.00 g, 28.7 mmol) and concentrated.The residue was dissolved in ethyl acetate (100 mL), washed with brine(50×2 mL), dried over anhydrous magnesium sulfate, concentrated andpurified by chromatography (eluting with petroleum ether) to give methyl4-bromo-5-methylthiophene-2-carboxylate (10.7 g, 72%) as a yellow solid:LCMS (ESI) m/z 235.0, 237.0 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ 7.69 (s,1H), 3.82 (s, 3H), 2.43 (s, 3H),

Step 2. Preparation of methyl4-bromo-5-(bromomethyl)thiophene-2-carboxylate

To a solution of methyl 4-bromo-5-methylthiophene-2-carboxylate (10.7 g,45.9 mmol) in carbon tetrachloride (200 mL) was added N-bromosuccinimide(9.7 g, 55.1 mmol) and 2,2′-Azobis(2-methylpropionitrile) (0.38 g, 2.30mmol). The reaction mixture was refluxed for 16 h, concentrated, andpurified by chromatography eluting with petroleum ether to give methyl4-bromo-5-(bromomethyl)thiophene-2-carboxylate (6.1 g, 43%) as a whitesolid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.79 (s, 1H), 4.92 (s, 2H), 3.84 (s,3H),

Step 3. Preparation of methyl4-bromo-5-((3,5-dichlorophenoxy)methyl)thiophene-2-carboxylate

A mixture of methyl 4-bromo-5-(bromomethyl)thiophene-2-carboxylate (6.1g, 19.6 mmol) and 3,5-dichlorophenol (3.2 g, 19.6 mmol) and potassiumcarbonate (8.3 g, 60.0 mmol) in DMF (200 mL) was stirred at roomtemperature for 16 h. The reaction mixture was filtered, diluted withethyl acetate (100×3 mL), washed with brine (150 mL), dried overanhydrous sodium sulfate and concentrated to give methyl4-bromo-5-((3,5-dichlorophenoxy)methyl)thiophene-2-carboxylate (7 g,90%) as a yellow solid: LCMS (ESI) m/z 395.1, 397.1 [M+1].

Step 4. Preparation of methyl4-cyclopropyl-5-((3,5-dichlorophenoxy)methyl)thiophene-2-carboxylate

A mixture of methyl4-bromo-5-((3,5-dichlorophenoxy)methyl)thiophene-2-carboxylate (100 mg,0.25 mmol), cyclopropylboronic acid (64 mg, 0.75 mmol), potassiumphosphate (265 mg, 1.25 mmol) and(1,1′-Bis(diphenylphosphino)ferrocene)dichloropalladium(II) (29 mg, 0.04mmol) in acetonitrile (20 mL) and water (1 mL), was stirred at 80° C.under nitrogen for 16 h. The reaction mixture was cooled down to roomtemperature, filtered, diluted with ethyl acetate (20 mL), andconcentrated. The residue was purified by chromatography (eluting with2-20% ethyl acetate in petroleum ether) to afford the target compound(60 mg, 66%) as a pale yellow oil: LCMS (ESI) m/z 357.0 [M+1].

Step 5. Preparation of4-cyclopropyl-5-((3,5-dichlorophenoxy)methyl)thiophene-2-carboxylic acid

A mixture of methyl4-cyclopropyl-5-((3,5-dichlorophenoxy)methyl)thiophene-2-carboxylate (60mg, 0.17 mmol) and lithium hydroxide (20 mg, 0.84 mmol) in THF (10 mL)and water (4 mL) was stirred at 50° C. for 16 h. The reaction mixturewas quenched with aqueous HCl (1N, 20 ml), extracted with ethyl acetate(20 mL×3), dried over anhydrous sodium sulfate and concentrated to givetarget compound (50 mg, 87%) as a yellow solid: LCMS (ESI) m/z 341.0[M−1].

Step 6. Preparation of (S)-methyl1-(4-cyclopropyl-5-((3,5-dichlorophenoxy)methyl)thiophene-2-carbonyl)pyrrolidine-2-carboxylate

A solution of4-cyclopropyl-5-((3,5-dichlorophenoxy)methyl)thiophene-2-carboxylic acid(50 mg, 0.14 mmol), (S)-methyl pyrrolidine-2-carboxylate hydrochloridesalt (36 mg, 0.22 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimidehydrochloride (54 mg, 0.28 mmol), 4-dimethylaminopyridine (51 mg, 0.42mmol) in dichloromethane (10 mL) was stirred at room temperature for 16h. The reaction mixture was quenched with HCl (1N, 20 mL), extractedwith dichloromethane (10 mL×3), dried over anhydrous sodium sulfate andconcentrated to give target compound (35 mg, 53%) as yellow oil: LCMS(ESI) m/z 454.0 [M+1].

Step 7. Preparation of(S)-1-(4-cyclopropyl-5-((3,5-dichlorophenoxy)methyl)thiophene-2-carbonyl)pyrrolidine-2-carboxylicacid

A mixture of(S)-methyl1-(4-cyclopropyl-5-((3,5-dichlorophenoxy)methyl)-thiophene-2-carbonyl)pyrrolidine-2-carboxylate(35 mg, 0.08 mmol), and lithium hydroxide (10 mg, 0.4 mmol) in THF (10mL) and water (4 mL) was stirred at 50° C. for 16 h. The reaction wasquenched with aqueous HCl (1 N, 20 mL), extracted with ethyl acetate (20mL×3) and concentrated. The residue was purified by prep-HPLC (0-35%acetonitrile in 5% HCOOH) to afford the title compound as a colorlesssolid (15 mg, 44%): LCMS (ESI) m/z 440.0 [M+1]: ¹H NMR (400 MHz,DMSO-d₆) δ 7.18 (m, 3H), 7.05 (m, 1H), 5.51-3.45 (m, 2H), 4.36-4.35 (m,1H), 3.80-3.76 (m, 1H), 3.50-3.45 (m, 1H), 2.11-1.75 (m, 5H), 0.95-0.88(m, 2H), 0.74-0.64 (m, 2H),

Example 135 Synthesisof(S)-1-(4-(((S)-1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

The compound was synthesized as described in Example 39: LCMS (ESI)Method A: RT=5.51 min, m/z 570.2 [M+1]; ¹H NMR (400 MHz, CD₃OD) δ 6.91(d, J=8.0 Hz, 1H), 6.79-6.64 (m, 3H), 4.42-4.39 (m, 1H), 3.90-3.87 (m,2H), 3.64-3.53 (m, 4H), 3.41-3.24 (m, 2H), 2.28-2.14 (m, 2H), 2.00-1.78(m, 5H), 1.27 (s, 3H), 0.84-0.69 (m, 2H), 0.52-0.49 (m, 2H),

Example 136 Synthesis of(S)-1-(4-(((R)-1-(5-chloro-4-(trifluoromethyl)pyridin-2-yl)-3-methylpyrrolidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

The compound was synthesized as described in Example 39: LCMS (ESI)Method A: RT=5.49 min, m/z 570.2 [M+1]; ¹H NMR (400 MHz, CD₃OD) δ 6.91(d, J=8.0 Hz, 1H), 6.77-6.64 (m, 3H), 4.44-4.41 (m, 1H), 3.90-3.87 (m,2H), 3.64-3.50 (m, 4H), 3.41-3.24 (m, 2H), 2.29-2.13 (m, 2H), 2.00-1.78(m, 5H), 1.27 (s, 3H), 0.83-0.69 (m, 2H), 0.54-0.47 (m, 2H),

Example 137a and Example 137b Synthesis of(4-(((R)-1-(3-chloro-5-fluorobenzyl)-3-methylpyrrolidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-prolineand(S)-1-(4-(((S)-1-(3-chloro-5-fluorobenzyl)-3-methylpyrrolidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

The compound was synthesized as described in Example 39: The enantiomerwas separated by chiral SFC from mixture of diastereomers using ChiralHPLC conditions as described in Example 113: The first eluting fractionof the title compound was arbitrarily assigned: LCMS (ESI) Method C:RT=4.86 min, m/z 533.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.30-7.14 (m3H), 6.94-6.72 (m, 2H), 4.36-4.10 (m, 1H), 3.91-3.78 (m, 2H), 3.65-3.61(m, 2H), 3.58-3.52 (m, 1H), 2.69-2.52 (m, 4H), 2.27-2.22 (m, 2H),1.99-1.79 (m, 5H), 1.60-1.54 (m, 1H), 1.21 (s, 3H), 0.85-0.81 (m, 2H),0.60-0.54 (m, 2H) and the second eluting fraction of the title compoundwas arbitrarily assigned: LCMS (ESI) Method C: RT=4.90 min, m/z 533.0[M+1]: ¹H NMR (400 MHz, DMSO-d₆) δ 7.30-7.14 (m, 3H), 6.94-6.72 (m, 2H),4.36-4.10 (m, 1H), 3.91-3.78 (m, 2H), 3.65-3.60 (m, 2H), 3.57-3.52 (m,1H), 2.69-2.52 (m, 4H), 2.28-2.22 (m, 2H), 2.00-1.79 (m, 5H), 1.60-1.55(m 1H), 1.19 (s, 3H), 0.87-0.81 (m 2H), 0.60-0.53 (m, 2H),

Example 138a and Example 138b Synthesis of(4S,5R)-3-[5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl]-5-methyl-oxazolidine-4-carboxylicacid and(4S,5R)-3-[5-cyclopropyl-[[1-[(1R)-1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl]-5-methyl-oxazolidine-4-carboxylicacid

The title compounds were synthesized as described in Example 225. Theenantiomer was separated by chiral SFC from mixture of diastereomersusing Chiral HPLC conditions as described in Example 113. The firsteluting fraction of the title compound was arbitrarily assigned: ¹H NMR(400 MHz, DMSO-d₆) δ 12.41 (s, 1H), 7.03-6.70 (m, 2H), 3.83 (dt, J=11.6,8.3 Hz, 2H), 3.57 (d, J=10.1 Hz, 2H), 2.22 (s, 2H), 2.03 (d, J=32.3 Hz,4H), 1.83 (s, 2H), 1.79-1.60 (m, 10H), 0.89 (dd, J=8.7, 2.2 Hz, 2H),0.57 (d, J=35.8 Hz, 2H); MS (ES+) m/z 454.2 (M+1) and the second eluentof the title compound was arbitrarily assigned: ¹H NMR (400 MHz,DMSO-d₆) δ 7.71 (t, J=1.9 Hz, 1H), 7.45 (d, J=1.9 Hz, 2H), 6.86 (dt,J=22.1, 10.6 Hz, 2H), 4.88-4.71 (m, 3H), 4.25-3.99 (m, 2H), 3.94-3.81(m, 2H), 3.01 (t, J=9.7 Hz, 2H), 2.36-2.25 (m, 1H), 2.12-1.94 (m, 2H),1.75 (t, J=17.7 Hz, 3H), 1.47-1.22 (m, 6H), 0.87 (d, J=8.5 Hz, 2H),0.66-0.50 (m, 2H): MS (ES+) m/z 633.2 (M).

Example 139a and Example 139b Synthesis of(S)-1-(4-(((S)-1-benzhydrylpyrrolidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid and(4-(((R)-1-benzhydrylpyrrolidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-proline

The compound was synthesized as described in Example 28: The enantiomerwas separated by chiral SFC from mixture of diastereomers using ChiralHPLC conditions as described in Example 113. The first eluting fractionwas arbitrarily assigned as (S)-1-(4-(((S)-1-benzhydrylpyrrolidin-3-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl) pyrrolidine-2-carboxylic acid:LCMS (ESI) Method C: RT=5.04 min, m/z 543.2 [M+1]: ¹H NMR (400 MHz,DMSO-d₆) δ 7.46-7.45 (m, 4H), 7.29-7.24 (m, 4H), 7.18-7.14 (m, 2H),6.93-6.71 (m, 2H), 4.35-4.32 (m, 1H), 4.25 (s, 1H), 4.01-3.94 (m, 2H),3.53-3.49 (m, 2H), 2.61-2.50 (m, 2H), 2.46-2.36 (m, 3H), 2.25-2.14 (m,1H), 1.98-1.79 (m, 5H), 1.63-1.57 (m, 1H), 0.81-0.72 (m, 2H), 0.55-0.48(m, 2H) and the second eluting fraction was arbitrarily assigned as thetitle compound: LCMS (ESI) Method C: RT=5.03 min, m/z 543.1 [M+1]; ¹HNMR (400 MHz, DMSO-ds) δ 12.5 (brs, 1H), 7.47-7.18 (m, 10H), 6.94-6.68(m, 2H), 4.36-4.33 (m, 4H), 3.55-3.35 (m, 2H), 2.73-2.53 (m, 2H),2.50-2.36 (m, 3H), 2.27-2.23 (m, 1H), 1.95-1.79 (m, 5H), 1.61 (brs, 1H),0.80-0.72 (m, 2H), 0.56-0.48 (m, 2H),

Example 140a and Example 140b Synthesis of(2S,4R)-1-[5-cyclopropyl-4-[[1-[(1R)-1-(3,5-dichlorophenyl)-2,2,2-trifluoro-ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl]-4-fluoro-pyrrolidine-2-carboxylicacid and(2S,4R)-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

The title compounds were synthesized as described in Example 92. Theenantiomer was separated by chiral SFC from mixture of diastereomersusing Chiral HPLC conditions as described in Example 113. The firsteluting fraction of the title compound was arbitrarily assigned: ¹H NMR(400 MHz, DMSO-d₆) δ 7.71 (q, J=1.9 Hz, 1H), 7.45 (d, J=1.8 Hz, 2H),6.89 (d, J=12.2 Hz, 1H), 6.86-6.71 (m, 1H), 5.43-5.14 (m, 1H), 4.77 (q,J=9.7 Hz, 1H), 4.47 (dd, J=9.3, 8.2 Hz, 1H), 4.00-3.80 (m 2H), 3.09-2.92(m, 2H), 2.38-1.89 (m, 4H), 1.86-1.62 (m, 3H), 1.46-1.28 (m, 2H),0.93-0.78 (m, 2H), 0.66-0.50 (m, 2H); MS (ES+) m/z 635.2 (M) and thesecond eluting fraction was arbitrarily assigned as the tile compound:¹H NMR (400 MHz, DMSO-d₆) δ 7.71 (t, J=1.9 Hz, 1H), 7.45 (d, J=1.9 Hz,2H), 6.89 (d, J=12.1 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H), 5.31 (dd, J=53.0,27.1 Hz, 1H), 4.76 (q, J=9.3 Hz, 1H), 4.48 (t, J=8.8 Hz, 1H), 3.95-3.81(m, 2H), 3.81-3.43 (m, 2H), 3.11-2.92 (m, 3H), 2.39-1.92 (m, 4H),1.86-1.65 (m, 3H), 1.48-1.28 (m, 2H), 0.92-0.77 (m, 2H), 0.66-0.51 (m,2H); MS (ES+) m/z 635.2 (M).

Example 141 Synthesis of(S)-1-(4-(1-benzhydrylazetidin-3-yloxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

The compound was synthesized as described in Example 28: LCMS (ESI)Method A: RT=5.06 min, m/z 515.2 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ 12.5(br s, 1H), 7.46-7.44 (m, 4H), 7.31-7.27 (m 4H), 7.21-7.17 (m, 2H),6.79-6.59 (m, 2H), 4.94-4.89 (m, 1H), 4.54 (s, 1H), 4.34-4.07 (m, 1H),3.71-3.49 (m, 3H), 3.27-3.23 (m, 1H), 3.01-2.99 (m, 2H), 2.26-2.21 (m,1H), 2.09-2.03 (m, 1H), 1.91-1.78 (m, 3H), 0.94-0.88 (m, 2H), 0.64-0.56(m, 2H),

Example 142a and Example 142b Synthesis of(4R,5S)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-thiazolidine-4-carboxylicacid and(4S,5S)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-thiazolidine-4-carboxylicacid Step 1. Preparation of methyl(2S,3R)-2-(benzenecarbonothioylamino)-3-hydroxy-butanoate

Triethylamine (4.1 mL, 29 mmol) was added to a mixture of methyl(2S,3R)-2-amino-3-hydroxy-butanoate (1.4 g, 11 mmol) in pyridine (10mL). The mixture was stirred for 5 min then 2-(benzothioylthio)aceticacid (2.4 g, 11 mmol) was added. The reaction was stirred at roomtemperature for 4 hours then diluted with dichloromethane (30 mL),washed with 1N hydrochloric acid (2×30 mL) and saturated aqueoussolution of sodium bicarbonate (2×30 mL). The organic phase was driedwith magnesium sulfate, filtered and concentrated to afford the titlecompound (2.38 g (89%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 8.20(d, J=8.6 Hz, 1H), 7.89-7.78 (m, 2H), 7.56-7.46 (m, 1H), 7.47-7.38 (m2H), 5.50 (dd, J=8.6, 2.3 Hz, 1H), 4.57 (qd, J=6.5, 2.3 Hz, 1H), 3.83(s, 3H), 1.35 (d, J=6.5 Hz, 3H); MS (ES+) m 253.9 (M).

Step 2. Preparation of methyl(4R,5S)-5-methyl-2-phenyl-4,5-dihydrothiazole-4-carboxylate

Xtalfluor-E(R) (913.2 mg, 3.95 mmol) was added to a solution of methyl(2S,3R)-2-(benzenecarbonothioylamino)-3-hydroxy-butanoate (500 mg, 1.97mmol) in dichloromethane (20 mL) and the mixture was stirred at roomtemperature for 2 h. The mixture was concentrated and purified by flashchromatography (0 to 100% EtOAc/Heptane gradient) to afford the titlecompound (240 mg, 52%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ7.95-7.81 (m, 2H), 7.54-7.45 (m, 1H), 7.45-7.37 (m, 2H), 5.14 (d, J=7.6Hz, 1H), 4.23 (dq, J=7.7, 7.0 Hz, 1H), 3.85 (s, 3H), 1.29 (d, J=7.0 Hz,3H); MS (ES+) m/z 236.0 (M+1).

Step 3. Preparation of (3S)-2-amino-3-sulfanyl-butanoic acidhydrochloride

Methyl (4R,5S)-5-methyl-2-phenyl-4,5-dihydrothiazole-4-carboxylate (240mg, 1.02 mmol) was stirred at 100° C. in 1 N hydrochloric acid (5 mL)for 16 h. The reaction was then cooled down and extracted with ethylether (2×20 mL). The aqueous phase was concentrated to give 175 mg (99%)of (3S)-2-amino-3-sulfanyl-butanoic acid hydrochloride as a white solid.The compound was used for next step without purification.

Step 4. Preparation of (5S)-5-methylthiazolidine-4-carboxylic acid

1,3,5-trioxane (275 mg, 3.06 mmol) was added to a mixture of methyl(3S)-2-amino-3-sulfanyl-butanoic acid hydrochloride (175 mg, 1.02 mmol)and triethylamine (0.28 mL, 2.04 mmol in toluene (3 mL). The mixture wasstirred at 65° C. until it turned to a mostly clear solution (4 h). Themixture was concentrated to dryness and the residue was taken up indichloromethane (15 mL). The organic phase was washed with a saturatedaqueous solution of sodium bicarbonate (25 mL), dried with magnesiumsulfate and concentrated to give a mixture of compounds, containing(5S)-5-methylthiazolidine-4-carboxylic acid, as a colorless oil. Themixture was carried on to next step without purification.

Step 5. Preparation of(4R,5S)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-thiazolidine-4-carboxylicacid and(4S,5S)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-thiazolidine-4-carboxylicacid

Following the procedure as described in Example 046. Step 1 and makingnon-critical variations as required to replace(2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid with(5S)-5-methylthiazolidine-4-carboxylic acid and the residue, a mixtureof diastereomers was separated by chiral SFC, the first compoundobtained(4R,5S)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-thiazolidine-4-carboxylicacid as a colorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 6.93-6.72 (m,2H), 4.79 (dd, J=31.8, 8.2 Hz, 1H), 4.60 (dd, J=9.4, 3.5 Hz, 1H), 3.83(dt, J=55.7, 6.9 Hz, 1H), 3.59 (d, J=13.0 Hz, 2H), 2.06-1.95 (m, 4H),1.69 (d, J=20.4 Hz, 11H), 1.32 (d, J=6.9 Hz, 1H), 1.23 (d, J=6.8 Hz,1H), 0.94-0.81 (m, 2H), 0.68-0.56 (m, 2H); MS (ES+) m/z 474.2 (M+1) andthe second compound obtained(4S,5S)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-thiazolidine-4-carboxylicacid as a colorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 6.95-6.77 (m,2H), 4.94 (d, J=9.3 Hz, 1H), 4.59-4.39 (m, 1H), 4.35 (d, J=9.4 Hz, 1H),3.84-3.70 (m, 1H), 3.60 (d, J=12.4 Hz, 2H), 2.07-1.93 (m, 4H), 1.78-1.59(m, 11H), 1.41 (d, J=6.7 Hz, 1H), 1.26 (d, J=6.8 Hz, 2H), 0.95-0.82 (m,2H), 0.66-0.49 (m, 2H); MS (ES+) m/z 474.2 (M+1).

Example 143 Synthesis of(4R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-1,1-dioxo-1,3-thiazolidine-4-carboxylicacid

3-chloroperoxybenzoic acid (42.9 mg 0.17 mmol) was added to a solutionof(4R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]thiazolidine-4-carboxylicacid (80 mg, 0.17 mmol) in dichloromethane (5 mL). The mixture wasstirred at ambient temperature for 48 hours. The mixture was thendiluted with dichloromethane (10 mL) and washed with a saturated aqueoussolution of sodium thiosulfate. The organic phase was dried withmagnesium sulfate, filtered, concentrated in vacuo. The residue waspurified by reverse-phase HPLC to afford the title compound (11.3 mg,13%) as a colorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 6.90 (t. J=9.9Hz, 2H), 5.29 (s, 1H), 4.69 (d, J=12.1 Hz, 2H), 4.49 (d, J=12.1 Hz, 2H),3.86 (q, J=15.3, 13.6 Hz, 2H), 3.62 (dp, J=7.2, 2.7 Hz, 4H), 2.58-2.50(m, 1H), 2.10-1.96 (m, 6H), 1.78-1.62 (m, 6H), 0.95-0.86 (m, 2H), 0.62(s, 2H): MS (ES+) m/z 491.2 (M+1).

Example 144 Synthesis of(2S,4S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4-cyano-pyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,4S)-1-(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-cyanopyrrolidine-2-carboxylate

Following the procedure as described in Example 046, Step 2 and makingnon-critical variations as required to replace(2S,4S)-4-hydroxypyrrolidine-2-carboxylic acid trifluoroacetic acid saltwith methyl (2S,4S)-4-cyanopyrrolidine-2-carboxylate trifluoroaceticacid, the title compound was obtained as a colorless solid: ¹H NMR (300MHz, CDCl₃) δ 7.37-7.32 (m, 3H), 6.89 (d, J=7.8 Hz, 1H), 6.32 (d, J=11.8Hz, 1H), 5.28 (s, 0.5H), 5.11 (s, 0.5H), 4.74 (t, J=8.2 Hz, 1H), 4.10(dd, J=13.6, 6.6 Hz, 1H), 3.90-3.52 (m, 6.5H), 3.32-3.21 (m, 1.5H),2.76-2.62 (m, 1H), 2.45-2.18 (m, 3H), 1.98-1.78 (m, 4H), 1.73-1.60 (m,4H), 0.84-0.74 (m, 2H), 0.58-0.45 (m, 2H); MS (ES+) m/z 582.0, 581.0(M+1).

Step 2. Preparation of(2S,4S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4-cyano-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(2S,4S)-1-(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-cyanopyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid: ¹H NMR (400 MHz,DMSO-d₆) δ 6.94-6.76 (m, 3H), 4.46 (q, J=8.3 Hz, 1H), 3.72 (dd, J=10.4,7.4 Hz, 1H), 3.67-3.46 (m, 5H), 3.43 (p, J=8.0 Hz, 1H), 2.75 (dt,J=12.5, 7.9 Hz, 1H), 2.24-1.97 (m, 4H), 1.78-1.63 (m, 6H), 0.89 (ddd,J=11.0, 8.2, 4.0 Hz, 2H), 0.67-0.53 (m, 3H); MS (ES+) m/z 467.2 (M+1).

Example 145 Synthesis of(2S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid Step 1. Preparation of4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride

Thionyl chloride (0.73 mL, 10.0 mmol) was added to a suspension of4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoic acid (860 mg, 2.50mmol) in dichloromethane (5 mL). 0.5 mL of DMF was added and the mixturewas stirred at room temperature for 30 minutes. The solution was thenconcentrated to afford the title compound (900 mg, 99.3%) as a colorlesssolid that was used for next step without purification.

Step 2. Preparation of(2S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid

A solution of(2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4,4-difluoro-pyrrolidine-2-carboxylicacid (155 mg, 0.41 mmol) was stirred with N,N-diisopropylethylamine(0.36 mL, 2.08 mmol) in DMF (1 mL) at 40° C. for 12 h. Then,4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride (50 mg,0.14 mmol) was added and the mixture was stirred at 40° C. for 10 min.The solvent was concentrated and purified by reverse-phase HPLC toafford the title compound (4.4 mg, 7%) as a colorless solid: ¹H NMR (400MHz, DMSO-d₆) δ 6.95-6.76 (m, 2H), 4.73-4.62 (m, 1H), 3.90-3.70 (m, 2H),3.60 (d, J=12.0 Hz, 2H), 2.98-2.82 (m, 1H), 2.10-1.94 (m, 4H), 1.79-1.58(m, 1H), 0.89 (t, J=9.4 Hz, 2H), 0.67-0.53 (m, 2H); MS (ES+) m/z 478.2(M+1).

Example 146 Synthesis of(1S,2S,4R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3-azabicyclo[2.2.1]heptane-2-carboxylicacid

4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride (50 mg,0.14 mmol) dissolved in dichloromethane (3 mL) was added to a solutionof (1S,2S,4R)-3-azabicyclo[2.2. I]heptane-2-carboxylic acidhydrochloride (36.7 mg, 0.21 mmol) and triethylamine (0.06 mL, 0.41mmol) in dichloromethane (3 mL). The mixture was stirred at ambienttemperature for 2 h and solvent was concentration. The residue waspurified by reverse-phase HPLC to afford the title compound (25.9 mg,50.2%) as a colorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 6.87 (d, J=12.0Hz, 1H), 6.83-6.64 (m, 1H), 3.88 (d, J=3.3 Hz, 2H), 3.65-3.53 (m, 2H),2.59-2.51 (m, 1H), 2.10-1.89 (m, 3H), 1.77-1.43 (m, 12H), 1.32-1.25 (m,1H), 0.95-0.81 (m, 2H), 0.65-0.51 (m, 2H): MS (ES+) m/z 468.2 (M+1).

Example 147 Synthesis of1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5,5-dimethyl-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith 5,5-dimethylpyrrolidine-2-carboxylic acid, the title compound wasobtained as a solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.70 (s, 1H), 6.76 (d,J=11.8 Hz, 1H), 6.62 (d, J=7.8 Hz, 1H), 4.01 (d, J=8.2 Hz, 1H), 3.56 (s,2H), 3.35 (s, 3H), 2.54 (s, 6H), 2.22-2.13 (m, 1H), 1.99 (dq, J=7.1,4.3, 3.6 Hz, 4H), 1.86-1.63 (m, 8H), 1.56 (s, 3H), 1.43 (s, 3H),0.93-0.82 (m, 2H), 0.55 (tt, J=5.3, 2.8 Hz, 2H): MS (ES+) m/z 470.2(M+1).

Example 148 Synthesis of(2S,4S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4-methyl-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (2S,4S)-4-methylpyrrolidine-2-carboxylic acid, the title compoundwas obtained as a solid: ¹H NMR (400 MHz. DMSO-d₆) δ 12.55 (s, 1H),6.90-6.71 (m, 2H), 4.32 (dd, J=9.6, 7.9 Hz, 1H), 3.63-3.53 (m, 2H),2.49-2.33 (m, 1H), 2.26-1.95 (m, 4H), 1.77-1.63 (m, 6H), 1.54-1.37 (m,1H), 1.02 (d, J=6.6 Hz, 1H), 0.98-0.82 (m, 2H), 0.66-0.53 (m, 2H); MS(ES+) m/z 456.2 (M+1).

Example 149 Synthesis of(2S,3S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3-methyl-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (2S,3S)-3-methylpyrrolidine-2-carboxylic acid, the title compoundwas obtained as a solid: ¹H NMR (400 MHz. DMSO-d₆) δ 12.64 (s, 1H),6.90-6.75 (m, 2H), 3.86 (d, J=7.2 Hz, 1H), 3.71-3.54 (m, 3H), 3.49-3.31(m, 2H), 2.37-2.18 (m, 1H), 2.01 (ddddd, J=18.4, 15.8, 12.2, 6.2, 3.9Hz, 4H), 1.78-1.63 (m, 6H), 1.52 (dddd, J=20.8, 16.7, 11.9, 7.4 Hz, 1H),1.15 (d, J=6.7 Hz, 3H), 1.05 (d, J=6.8 Hz, 1H), 0.98-0.81 (m, 2H), 0.58(ddq, J=14.4, 5.4, 3.0, 2.2 Hz, 2H); MS (ES+) m/z 456.2 (M+1).

Example 150 Synthesis of(2S,4R)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4-methyl-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (2S,4R)-4-methylpyrrolidine-2-carboxylic acid, the title compoundwas obtained as a solid: ¹H NMR (400 MHz. DMSO-d₆) δ 6.86 (d, J=12.0 Hz,1H), 6.83-6.78 (m, 1H), 4.38 (dd, J=8.8, 3.5 Hz, 1H), 3.60 (s, 2H), 3.57(s, 1H), 3.44 (dd, J=10.0, 7.0 Hz, 1H), 2.89 (dd, J=10.1, 7.8 Hz, 1H),2.09-1.94 (m, 6H), 1.93-1.80 (m, 1H), 1.76-1.59 (m, 12H), 1.02 (d, J=6.6Hz, 1H), 0.92 (d, J=6.7 Hz, 3H), 0.90-0.83 (m, 2H), 0.58 (ddt, J=15.2,5.3, 2.8 Hz, 2H): MS (ES+) m/z 456.2 (M+1).

Example 151 Synthesis of(2R)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3,3-dimethyl-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (S)-3,3-dimethylpyrrolidine-2-carboxylic acid, the title compoundwas obtained as a solid: ¹H NMR (400 MHz, DMSO-d₆) δ 6.86 (d, J=12.1 Hz,1H), 6.84-6.81 (m, 1H), 3.59 (d, J=12.2 Hz, 3H), 2.01 (d, J=16.5 Hz,4H), 1.84-1.58 (m, 11H), 1.16 (s, 2H), 1.04 (d, J=9.1 Hz, 3H), 0.96 (s,1H), 0.89 (ddt, J=9.6, 7.6, 4.9 Hz, 2H), 0.67-0.51 (m, 2H); MS (ES+) m/z470.2 (M+1).

Example 152 Synthesis of(2S,5R)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (2S,5R)-5-methylpyrrolidine-2-carboxylic acid, the title compoundwas obtained as a solid: MS (ES+) m/z 456.2 (M+1).

Example 153 Synthesis of(2S,5S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (2S,5S)-5-methylpyrrolidine-2-carboxylic acid, the title compoundwas obtained as a solid: MS (ES+) m/z 456.2 (M+1).

Example 154 Synthesis of(4R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]oxazolidine-4-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (S)-oxazolidine-4-carboxylic acid, the title compound was obtainedas a solid: ¹H NMR (400 MHz. DMSO-d₆) δ 13.06 (s, 1H), 6.89 (d, J=13.6Hz, 2H), 4.80 (s, 1H), 4.33 (d, J=14.2 Hz, 1H), 3.61 (s, 2H), 2.10-1.95(m, 4H), 1.77-1.62 (m, 10OH), 0.90 (dd, J=8.5, 2.0 Hz, 2H), 0.61 (s,2H), MS (ES+) m/z 444.2 (M+1).

Example 155 Synthesis of(4R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5,5-dimethyl-thiazolidine-4-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (R)-5,5-dimethylthiazolidine-4-carboxylic acid, the title compoundwas obtained as a solid: ¹H NMR (400 MHz, DMSO-d₆) δ6.94-6.81 (m, 2H),4.91 (d, J=9.6 Hz, 1H), 4.66 (d, J=9.7 Hz, 1H), 4.48 (d, J=9.5 Hz, 1H),4.41 (s, 1H), 3.60 (d, J=11.7 Hz, 2H), 2.09-1.96 (m, 4H), 1.77-1.63 (m,8H), 1.58 (s, 1H), 1.43 (d, J=3.3 Hz, 6H), 1.34 (s, 1H), 0.90 (td,J=8.3, 7.5, 5.4 Hz, 2H), 0.64 (td, J=5.8, 3.8 Hz, 1H), 0.58 (s, 1H): MS(ES+) m/z 488.2 (M+1).

Example 156 Synthesis of(1R,3S,5R)-4-[5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl]-4-azabicyclo[3.1.0]hexane-3-carboxylicacid Step 1. Preparation of5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoylchloride

Following the procedure as described in Example 145, Step 1 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoic acid with4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoic acid, the titlecompound was obtained as solid that was used directly without anyfurther analytical characterization.

Step 2. Preparation of(1R,3S,5R)-4-[5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl]-4-azabicyclo[3.1.0]hexane-3-carboxylicacid

Following the procedure as described in Example 145. Step 2 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoylchloride and (1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acidhydrochloride with (1R,3S,5R)-2-azabicyclo[3.1.0]hexane-3-carboxylicacid, the title compound was obtained as a solid: ¹H NMR (400 MHz,DMSO-d₆) δ 7.47 (t. J=1.9 Hz, 1H), 7.36 (d, J=2.0 Hz, 2H), 6.92-6.85 (m,2H), 4.22 (dd, J=9.2, 5.5 Hz, 1H), 3.94-3.86 (m, 2H), 3.56 (q, J=6.7 Hz,1H), 3.15-3.06 (m, 1H), 2.93 (d, J=10.9 Hz, 1H), 2.79 (d, J=11.1 Hz,1H), 2.37-2.26 (m, 1H), 2.16 (dt, J=12.8, 6.1 Hz, 1H), 2.08-1.85 (m,4H), 1.83-1.65 (m, 4H), 1.41-1.31 (m, 2H), 1.30 (d, 3H), 0.89 (dd,J=8.3, 2.2 Hz, 2H), 0.73-0.53 (m, 4H); MS (ES+) m/z 575.2 (M+1).

Example 157 Synthesis of(2S,3S)-1-[5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl]-3-methyl-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoylchloride and (1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acidhydrochloride with oxazolidine-4-carboxylic acid, the title compound wasobtained as a solid: ¹H NMR (4 00 MHz, DMSO-d₆) δ 12.57 (s, 1H), 7.46(t, J=1.9 Hz, 1H), 7.36 (d, J=1.9 Hz, 2H), 6.91-6.76 (m, 2H), 3.87 (dd,J=14.9, 6.3 Hz, 3H), 3.67-3.50 (m, 2H), 2.93 (d, J=10.8 Hz, 1H), 2.78(d, J=11.1 Hz, 1H), 2.27 (dq, J=15.4, 7.1, 6.6 Hz, 1H), 2.11-1.86 (m,4H), 1.83-1.70 (m, 4H), 1.49 (dq, J=11.8, 8.4 Hz, 2H), 1.42-1.25 (m,5H), 1.14 (d, J=6.7 Hz, 2H), 1.04 (d, J=6.8 Hz, 1H), 0.92-0.80 (m, 2H),0.63-0.50 (m, 2H): MS (ES+) m/z 577.2 (M+1).

Example 158 Synthesis of(2S,4R)-1-[5-cyclopropyl-4-[[1-(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl-4-fluoro-pyrrolidine-2-carboxylic acid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace4-(l-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoylchloride and (1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acidhydrochloride with (2S,4R)-4-fluoropyrrolidine-2-carboxylic acid, thetitle compound was obtained as a colorless solid: ¹H NMR (400 MHz,DMSO-d₆) δ 7.47 (t. J=1.8 Hz, 1H), 7.36 (d, J=1.9 Hz, 2H), 6.96-6.71 (m,2H), 5.29 (dd, J=53.3, 18.4 Hz, 1H), 4.47 (t, J=9.2, 8.1 Hz, 1H),3.97-3.61 (m, 4H), 2.93 (d, J=10.9 Hz, 1H), 2.79 (d, J=10.9 Hz, 1H),2.06-1.85 (m, 3H), 1.85-1.66 (m, 3H), 1.43-1.21 (m, 5H), 1.02 (t, J=7.2Hz, 1H), 0.92-0.80 (m, 2H), 0.64-0.51 (m, 2H); MS (ES+) m/z 581.2 (M+1).

Example 159 Synthesis of(4R)-3-[5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl]thiazolidine-4-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoylchloride and (1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acidhydrochloride with (R)-thiazolidine-4-carboxylic acid, the titlecompound was obtained as a solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.47 (t.J=2.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 2H), 6.91 (d, J=12.3 Hz, 1H), 6.84 (s,2H), 4.42 (s, 2H), 3.89 (s, 3H), 3.56 (q, J=6.8 Hz, 2H), 3.37 (s, 6H),3.27 (s, 2H), 3.19 (s, 2H), 2.94 (d, J=11.0 Hz, 2H), 2.79 (d, J=11.1 Hz,2H), 2.55 (dd, J=4.2, 2.3 Hz, 3H), 2.45 (dt, J=3.7, 1.9 Hz, 1H),2.03-1.87 (m, 4H), 1.83-1.70 (m, 4H), 1.29 (d, J=6.7 Hz, 6H), 0.86 (d,J=8.4 Hz, 2H), 0.60 (s, 2H): MS (ES+) m/z 581.2 (M+1).

Example 160 Synthesis of(2S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4,4-difluoro-pyrrolidine-2-carboxylicacid

A solution of(2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4,4-difluoro-pyrrolidine-2-carboxylicacid (155 mg, 0.41 mmol) was stirred with N,N-diisopropylethylamine(0.36 mL, 2.08 mmol) in N,N-dimethylformamide (1 mL) at 40° C. for 12 h.To this reaction mixture4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride (50 mg,0.14 mmol) was added and the mixture was stirred at 40° C. for 10 min.The solvent was concentrated in vacuo. The residue was purified byreverse-phase HPLC to afford the title compound (4.4 mg, 7%) as acolorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 6.95-6.76 (m, 2H),4.73-4.62 (m, 1H), 3.90-3.70 (m, 2H), 3.60 (d, J=12.0 Hz, 2H), 2.98-2.82(m, 1H), 2.10-1.94 (m, 4H), 1.79-1.58 (m, 11H), 0.89 (t, J=9.4 Hz, 2H),0.67-0.53 (m, 2H); MS (ES+) m/z 478.2 (M+1).

Example 161 Synthesis of(2S,4S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-4-hydroxy-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 160 and makingnon-critical variations as required to replace(2S)-1-(9H-fluoren-9-ylmethoxycarbonyl)-4,4-difluoro-pyrrolidine-2-carboxylicwith(2S,4S)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)-4-hydroxypyrrolidine-2-carboxylicacid, the title compound was obtained as a colorless solid: ¹H NMR (400MHz, DMSO-d₆) δ 6.88-6.77 (m, 2H), 6.77-6.71 (m, 2H), 4.26 (dd, J=9.0,4.4 Hz, 1H), 4.12 (dq, J=14.1, 4.7 Hz, 2H), 3.83 (d, J=9.1 Hz, 1H),3.65-3.53 (m, 5H), 3.15 (dd, J=10.5, 3.9 Hz, 1H), 2.28 (td, J=8.7, 4.5Hz, 1H), 2.22-2.13 (m, 1H), 2.08-1.94 (m, 4H), 0.94-0.79 (m, 4H),0.68-0.53 (m, 1H); MS (ES+) m/z 458.2 (M+1).

Example 162 Synthesis of(4S,5R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-oxazolidine-4-carboxylicacid Step 1. Preparation of methyl(4S,5R)-5-methyloxazolidine-4-carboxylate

1,3,5-trioxane (797 mg, 8.84 mmol) was added to a mixture of methyl(2S,3R)-2-amino-3-hydroxy-butanoate hydrochloride (500 mg, 2.95 mmol)and triethylamine (0.82 mL, 5.89 mmol in toluene (5 mL). The mixture wasstirred at 65° C. until it turned to a mostly clear solution (4 h). Themixture was concentrated to dryness and the residue was taken up indichloromethane (15 mL). The organic phase was washed with a saturatedaqueous solution of sodium bicarbonate (25 mL), dried with magnesiumsulfate and concentrated in vacuo to afford the title compound ascolorless oil. This residue was used in the next step withoutpurification and analytical characterization.

Step 2. Preparation of methyl(4S,5R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluorobenzoyl]-5-methyl-oxazolidine-4-carboxylate

A solution of 4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoylchloride (250 mg, 0.69 mmol) dissolved in acetonitrile (2 mL) was addeddropwise to a solution of methyl(4S,5R)-5-methyloxazolidine-4-carboxylate (50 mg, 0.34 mmol) in a 1:1mixture of acetonitrile (2 mL) and sodium carbonate (15 mass %) in water(2 mL). The mixture was stirred at ambient temperature for 2 hours andthe solvent was concentrated in vacuo. The residue was redissolved indichloromethane (25 mL), washed with a saturated aqueous solution ofsodium bicarbonate (25 mL), dried with magnesium sulfate andconcentrated in vacuo to afford the title compound (115 mg, 71%) as acolorless solid which was used in the next step without purification: MS(ES+) m/z 472.2 (M+1).

Step 3. Preparation of(4S,5R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-oxazolidine-4-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(4S,5R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-oxazolidine-4-carboxylateand following the residue was purified by reverse-phase HPLC, the titlecompound was obtained as a colorless solid (110 mg, 99%): ¹H NMR (400MHz, DMSO-d₆) δ 6.97-6.69 (m, 2H), 4.81 (s, 1H), 4.26-3.96 (m, 1H), 3.59(d, J=17.2 Hz, 2H), 1.99 (s, 3H), 1.69 (d, J=20.0 Hz, 10H), 1.39 (d,J=6.0 Hz, 1H), 1.27 (d, J=6.1 Hz, 1H), 0.90 (d, J=9.8 Hz, 2H), 0.71-0.51(m, 2H): MS (ES+) m, 458.2 (M+1).

Example 163 Synthesis of(4R,5S)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-5-methyl-oxazolidine-4-carboxylicacid

Following the procedure as described in Example 162. Step 2 and Step 3and making non-critical variations as required to replace methyl(4S,5R)-5-methyloxazolidine-4-carboxylate with methyl(4R,5S)-5-methyloxazolidine-4-carboxylate, the title compound was obtainas a colorless solid: MS (ES+) m/z 458.2 (M+1).

Example 164 Synthesis of(4S,5R)-3-[5-cyclopropyl-4-[[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoyl-5-methyl-oxazolidine-4-carboxylicacid

Following the procedure as described in Example 162, Step 2 and Step 3and making non-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-piperidyl]methoxy]-2-fluoro-benzoylchloride, the title compound was obtain as a colorless solid: ¹H NMR(400 MHz, DMSO-d₆) δ 7.47 (t. J=1.9 Hz, 1H), 7.36 (d, J=2.0 Hz, 2H),6.97-6.77 (m, 2H), 4.83 (s, 2H), 4.10 (dd, J=32.1, 8.0 Hz, 2H), 3.89 (d,J=12.5 Hz, 2H), 3.58 (d, J=7.0 Hz, 1H), 3.00-2.72 (m, 3H), 2.10-1.88 (m,3H), 1.85-1.67 (m, 3H), 1.35 (dd, J=45.3, 6.3 Hz, 10H), 0.87 (d, J=8.3Hz, 2H), 0.59 (d, J=10.5 Hz, 2H): MS (ES+) m/z 479.2 (M+1).

Example 165 Synthesis of(4S,5R)-3-[5-cyclopropyl-4-[(3,5-dichlorophenoxy)methyl]-2-fluorobenzoyl]-5-methyl-oxazolidine-4-carboxylicacid

Following the procedure as described in Example 162, Step 2 and Step 3and making non-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with5-cyclopropyl-4-((3,5-dichlorophenoxy)methyl)-2-fluorobenzoyl chloride,the title compound was obtain as a colorless solid: ¹H NMR (400 MHz,DMSO-d₆) δ 7.39 (dd, J=30.9, 10.5 Hz, 1H), 7.25 (dd, J=3.9, 1.8 Hz, 2H),7.23-7.18 (m, 1H), 7.05 (dd, J=10.6, 6.7 Hz, 1H), 5.32 (d, J=17.6 Hz,2H), 4.90-4.79 (m, 1H), 4.21 (dt, J=23.3, 6.2 Hz, 1H), 4.08 (d, J=7.5Hz, 1H), 2.10-1.92 (m, 1H), 1.42 (d, J=6.0 Hz, 3H), 1.31 (d, J=6.1 Hz,1H), 0.93 (ddd, J=10.4, 8.3, 1.9 Hz, 2H), 0.75-0.58 (m, 2H): MS (ES+)m/z 468.1 (M+1).

Example 166 Synthesis of(4S,5R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-2,5-dimethyl-oxazolidine-4-carboxylicacid

Following the procedure as described in Example 162. Step 2 and Step 3and making non-critical variations as required to replace methyl(4S,5R)-5-methyloxazolidine-4-carboxylate with(4S,5R)-2,5-dimethyloxazolidine-4-carboxylic acid, the title compoundwas obtain as a colorless solid: the title compound was obtain as acolorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 6.83 (dd, J=17.0, 10.2 Hz,2H), 5.55 (d, J=6.9 Hz, 1H), 4.52-4.34 (m, 1H), 3.59 (s, 2H), 2.02 (d,J=18.8 Hz, 4H), 1.80-1.60 (m, 11H), 1.50-1.04 (m, 6H), 0.89 (t, J=7.4Hz, 2H), 0.59 (d, J=14.6 Hz, 2H): MS (ES+) m/z 472.2 (M+1).

Example 167 Synthesis of1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-2,3-dihydropyrrole-5-carboxylicacid Step 1. Preparation of methyl1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-2,3-dihydropyrrole-5-carboxylate

To a solution of methyl (2S)-pyrrolidine-2-carboxylate hydrochloride(300 mg, 1.81 mmol) in dichloromethane (10 mL) at 0° C. (stirringvigorously), triethylamine (0.55 mL, 3.98 mmol) was added, followed byN-chlorosuccinimide (266 mg, 1.99 mmol) in small portions. The solutionwas stirred at ambient temperature for 15 min. Pyridine (0.34 mL, 4.17mmol) was then added slowly and the reaction was allowed to stir for 30min. The mixture was cooled to −40° C. and4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride (1.45 g,3.98 mmol) was added slowly. The mixture was allowed to warm up toambient temperature and stirred for 48 hours.

The mixture was diluted with dichloromethane (20 mL) and was washed with1N hydrochloric acid and aqueous sodium bicarbonate. The organic phasewas dried with magnesium sulfate, concentrated and purified by flashchromatography eluting with gradient 0 to 80% of ethyl acetate inheptane gradient to afford the title compound (215 mg, 26%) as acolorless solid: MS (ES+) m/z 454.2 (M+1).

Step 3. Preparation of1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-2,3-dihydropyrrole-5-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-2,3-dihydropyrrole-5-carboxylateand following the residue was purified by reverse-phase HPLC, the titlecompound was obtained as a colorless solid (25.2 mg, 69%): ¹H NMR (400MHz. DMSO-d₆) δ 12.85 (s, 1H), 6.93-6.75 (m, 2H), 6.13-5.97 (m, 1H),5.87 (ddq, J=30.0, 6.4, 2.2 Hz, 1H), 5.14-4.77 (m, 1H), 4.35-3.95 (m,2H), 3.66-3.55 (m, 2H), 2.10-1.96 (m, 4H), 1.78-1.63 (m, 12H), 0.89(tdd, J=7.7, 3.9, 2.0 Hz, 2H), 0.60 (ddt, J=13.1, 5.3, 2.5 Hz, 2H); MS(ES+) m/z 440.2 (M+1).

Example 168a and Example 168b Synthesis of(2S,3S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3-ethyl-pyrrolidine-2-carboxylicacid and(2R,3R)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3-ethyl-pyrrolidine-2-carboxylicacid Step 1. Preparation of 1-benzyl 2-methyl4,5-dihydro-1H-pyrrole-1,2-dicarboxylate

To a solution of methyl (2S)-pyrrolidine-2-carboxylate hydrochloride 2.0g, 12 mmol) in dichloromethane (60 mL) at 0° C. (stirring vigorously),triethylamine (3.7 mL, 27 mmol) was added, followed byN-chlorosuccinimide (1.8 g, 13 mmol) in small portions. The solution wasstirred at room temperature for 4 h. Pyridine (2.2 mL, 28 mmol) was thenadded slowly and the reaction was allowed to stir for 30 min. Themixture was cooled to −40° C. and benzyl chloroformate (3.9 mL, 27 mmol)was added slowly. The mixture was allowed to warm to ambient temperatureand stirred for 48 h. The mixture was diluted with dichloromethane (20mL) and was washed with 1N hydrochloric acid and aqueous sodiumbicarbonate. The organic phase was dried with magnesium sulfate andconcentrated in vacuo. The residue was purified by flash chromatographyeluting with gradient 0 to 80% of ethyl acetate in heptane to afford thetitle compound (2.71 g, 86%) as pale yellow oil: MS (ES+) m/z 262.2(M+1).

Step 2. Preparation of 1-benzyl 2-methyl(2S)-3-vinylpyrrolidine-1,2-dicarboxylate

Copper (I) bromide-dimethyl sulfide (39.3 mg, 0.19 mmol) was added to asolution of vinylmagnesium chloride (0.9 mL, 1.43 mmol, 1.6 M intetrahydrofuran) in tetrahydrofuran (5 mL) at −40° C. The mixture wasstirred at −40° C. for 3 h. A solution of 1-benzyl-5-methyl2,3-dihydropyrrole-1,5-dicarboxylate (250 mg, 0.96 mmol) intetrahydrofuran 1.0 N (5 mL) was added dropwise to the mixture at −40°C. The reaction was warm to ambient temperature over 5 hours. Thereaction was quenched with addition of saturated ammonium chloride andextracted with dichloromethane (2×20 mL). The organic phase was driedwith magnesium sulfate, filtered, concentrated on silica gel andpurified by flash chromatography eluting with gradient 0 to 100% ofethyl acetate in heptane to afford the title compound as pale yellowoil: MS (ES+) m/Z 290.1 (M+1).

Step 3. Preparation of methyl (2S)-3-ethylpyrrolidine-2-carboxylate

A mixture of 1-benzyl 2-methyl (2S)-3-vinylpyrrolidine-1,2-dicarboxylate(175 mg, 0.60 mmol) and palladium, 10% on carbon (64.36 mg, 0.06 mmol)in methanol (5 mL) was stirred overnight under an atmosphere ofhydrogen. The mixture was then filtered over celite and washed withmethanol. The filtrate was concentrated to afford the title compound (45mg, 47%) as a colorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 3.69-3.54 (m,3H), 2.91-2.76 (m, 2H), 2.00-1.79 (m, 1H), 1.53 (tt, J=13.3, 7.4 Hz,1H), 1.39-1.21 (m, 2H), 0.88 (td, J=7.4, 3.5 Hz, 3H),

Step 4. Preparation methyl(2S)-1-(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-ethylpyrrolidine-2-carboxylate

A solution of methyl (2S)-3-ethylpyrrolidine-2-carboxylate (45 mg, 0.29mmol) in N,N-dimethylformamide (1 mL) was added to a solution of4-(l-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoic acid (99 mg, 0.29mmol), HATU (131 mg, 0.34 mmol) and N,N-diisopropylethylamine (0.07 mL,0.43 mmol) in N,N-dimethylformamide (1 mL). The reaction mixture wasstirred at ambient temperature for 2 hours. A saturated aqueous solutionof sodium bicarbonate was then added and the aqueous phase was extractedwith dichloromethane (2×15 mL). The organic phase was dried withmagnesium sulfate, filtered and concentrated to afford the titlecompound (135 mg, 97%) as colorless oil that was carried to next stepwithout purification.

Step 5. Preparation of(2S,3S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3-ethyl-pyrrolidine-2-carboxylicacid and(2R,3R)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3-ethyl-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith(2S)-1-(4-(((3S,5S,7S)-adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-ethylpyrrolidine-2-carboxylateand following the residue was purified by SFC chiral separation toobtain first title compound (15.9 mg, 12%) as colorless solid: ¹H NMR(400 MHz, DMSO-d₆) δ 6.94-6.75 (m, 2H), 3.95 (d, =6.6 Hz, 1H), 3.59 (d,J=9.4 Hz, 2H), 2.21-1.89 (m, 4H), 1.80-1.58 (m, 8H), 1.56-1.30 (m, 2H),1.05-0.76 (m, 4H), 0.67-0.45 (m, 2H): MS (ES+) m/z 470.2 (M+1) and thesecond compound as a colorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.55(s, 1H), 6.90-6.76 (m, 2H), 3.71-3.55 (m, 2H), 2.18-1.92 (m, 6H),1.77-1.29 (m, 10H), 1.23 (d, J=5.1 Hz, 1H), 0.99-0.81 (m, 5H), 0.57(dtd, J=19.9, 5.7, 3.8 Hz, 2H); MS (ES+) m/z 470.2 (M+1).

Example 169 Synthesis of(2S,4R)-4-chloro-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 145. Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (2S,4R)-4-chloropyrrolidine-2-carboxylic acid, the title compoundwas obtained as a colorless solid (0.026 g, 10% yield): ¹H NMR (400 MHz,DMSO-d₆) δ 7.46 (q, J=2.0 Hz, 1H), 7.36 (d, J=2.0 Hz, 3H), 6.90 (d,J=12.1 Hz, 1H), 6.86-6.72 (m 2H), 6.68 (s, 1H), 4.70 (s, 2H), 4.52 (t,J=8.4 Hz, 1H), 3.93-3.73 (m, 5H), 3.61-3.50 (m, 2H), 3.39 (d, J=12.6 Hz,1H), 2.93 (d, J=11.1 Hz, 2H), 2.78 (d, J=10.9 Hz, 2H),2.50-2.32 (m, 3H),2.07-1.86 (m, 5H), 1.76 (dd, J=20.4, 13.0 Hz, 5H), 1.39-1.21 (m, 9H),0.89-0.84 (m, 3H), 0.61-0.56 (m, 3H); MS (ES−) m/z 613 (M−1).

Example 170 Synthesis(2S)-2-[[4-(I-adamantylmethoxy)-5-cyclopropyl-2-fluorobenzoyl]amino]-2-cyclobutyl-aceticacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (S)-2-amino-2-cyclobutylacetic acid, the title compound wasobtained as a colorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 7.95 (dd,J=7.8, 5.1 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 6.87 (d, J=13.2 Hz, 1H),4.31 (t, J=8.0 Hz, 1H), 3.63 (s, 2H), 2.71 (q, J=8.2 Hz, 1H), 2.58-2.51(m, 1H), 2.45 (p, J=1.8 Hz, 1H), 2.09-1.97 (m, 4H), 1.96-1.62 (m, 17H),0.95-0.86 (m, 2H), 0.65-0.56 (m, 2H); MS (ES+) m/z 456.4 (M+1).

Example 171 Synthesis of3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3-azabicyclo[3.1.0]hexane-4-carboxylicacid Step 1. Preparation of(1S,2S,5R)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid trifluoroaceticacid salt

A solution of lithium diisopropylamide (0.13 mL, 0.26 mmol, 2.0 Msolution in tetrahydrofuran) was added dropwise to a solution ofcis-3-tert-butoxycarbonyl-3-azabicyclo[3.1.0]hexane-4-carboxylic acid(30 mg, 0.12 mmol) in tetrahydrofuran (0.6 mL) at −40° C. After 5minutes the reaction was warmed to room temperature and stirred for 1.5h. The reaction was quenched with 10% aqueous HCl (1 mL), extracted withethyl acetate, dried over anhydrous sodium sulfate and concentrated invacuo. The crude mixture of diastereomers (˜1:1 by LCMS) was redissolvedin dichloromethane (3 mL) and trifluoroacetic acid (0.09 mL, 1.18 mmol)was added dropwise at room temperature. After 2.5 hours the reaction wasconcentrated in vacuo to afford the title compound that was used in thenext step without further purification.

Step 2. Preparation of3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3-azabicyclo[3.1.0]hexane-4-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (2S,4R)-4-chloropyrrolidine-2-carboxylic acid, the title compoundwas obtained as a colorless solid (3.2 mg, 6% yield): MS (ES+) m % z454.3 (M+1).

Example 172 Synthesis of(2R,3R,6R)-1-(5-cyclopropyl-4-((1-((R)-1-(3,5-dichlorophenyl)ethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)octahydrocyclopenta[b]pyrrole-2-carboxylicacid

Following the procedure as described in Example 145, Step 2 and makingnon-critical variations as required to replace(1S,2S,4R)-3-azabicyclo[2.2.1]heptane-2-carboxylic acid hydrochloridewith (2S,4R)-4-chloropyrrolidine-2-carboxylic acid, the title compoundwas obtained as a colorless solid (0.0064 g, 20%): MS (ES+) m/z 605.1,603.1 (M+1).

Example 173 Synthesis of(2S,4R)-1-(4-((1-(3-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of methyl4-((1-(3-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate

To a solution of methyl5-cyclopropyl-2-fluoro-4-(4-piperidylmethoxy)benzoate (0.090 g, 0.29mmol) in 4-methyl-2-pentanone (9 mL),[3-chloro-5-(trifluoromethyl)phenyl]methyl methanesulfonate (0.10 g,0.35 mmol) was added. To this reaction mixture, water (I mL) was addedfollowed by potassium carbonate (0.061 g, 0.44 mmol). The reactionmixture was heated at 60° C. and stirred for 24 h. The crude solutionwas cooled to room temperature, diluted with water and was extractedwith ethyl acetate (3×10 mL). The organic layer was separated, driedwith anhydrous magnesium sulfate and concentrated in vacuo. The residuewas purified by column chromatography eluting with ethyl acetate inhexanes to afford pale yellow oil (0.046 g, 32% yield): ¹H NMR (400 MHz,CDCl₃) δ 7.57-7.41 (m, 4H), 6.54 (d, J=12.7 Hz, 1H), 3.92-3.83 (m, 5H),3.53 (s, 2H), 2.90 (dt, J=11.2, 2.9 Hz, 2H), 2.13-1.97 (m, 3H),1.98-1.80 (m, 3H), 1.56-1.41 (m, 2H), 1.26 (s, 1H), 0.95-0.82 (m, 2H),0.71-0.60 (m, 2H),

Step 4. Preparation of4-((1-(3-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl4-[[1-[[3-chloro-5-(trifluoromethyl)phenyl]methyl]-4-piperidyl]methoxy]-5-cyclopropyl-2-fluoro-benzoate,the title compound (0.48 g, 95% yield) was obtained as a colorlesssolid: MS (ES−) m/z 484 (M−1).

Step 5. Preparation of4-((1-(3-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride

Following the procedure as described in Example 046, Step 1 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoic acid with4-((1-(3-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a pale yellow solid that wasused in the next step without purification.

Step 6. Preparation of(2S,4R)-1-(4-((1-(3-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 046, Step 2 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with4-((1-(3-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acidtrifluoroacetic acid salt with (2S,4R)-4-fluoropyrrolidine-2-carboxylicacid hydrochloric acid salt, the title compound (0.009 g, 29% yield) wasobtained as a colorless solid: ¹H NMR (400 MHz, DMSO-d₆) δ 12.77 (s,1H), 7.24 (s, 2H), 7.11 (s, 2H), 6.84 (d, J=8.0 Hz, 4H), 4.49 (dd,J=9.4, 8.1 Hz, 1H), 3.94 (s, 2H), 3.71-3.55 (m, 2H), 3.53-3.32 (m, 24H),3.27 (s, 1H), 2.84 (s, 1H), 2.67 (t, J=1.9 Hz, 1H), 2.54 (d, J=2.4 Hz,4H), 2.03 (ddd, J=14.1, 8.6, 5.4 Hz, 2H), 1.82 (s, 4H), 1.41 (s, 2H),1.29-1.21 (m, 1H), 0.87 (ddt, J=9.2, 6.3, 4.5 Hz, 2H), 0.60 (tt, J=8.7,4.3 Hz, 2H); MS (ES+) m/z 601.2 (M+1).

Example 174 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-(2,4-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 173. Step 2-6, andmaking non-critical variations as required to replace(3-chloro-5-(trifluoromethyl)phenyl)methanol in Step 2 with(2,4-dichlorophenyl)methanol, the title compound was obtained as acolorless solid (0.042 g, 43% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 12.75(s, 1H), 7.61-7.54 (m, 2H), 7.43 (dd, J=8.4, 2.2 Hz, 1H), 6.96-6.78 (m,2H), 6.51 (s, 1H), 4.49 (dd, J=9.5, 8.1 Hz, 1H), 3.89 (dt, J=14.2, 5.0Hz, 3H), 3.13 (d, J=10.3 Hz, 1H), 2.72 (d, J=13.2 Hz, 1H), 2.66-2.51 (m,1H), 2.28-1.93 (m, 3H), 1.83 (t, J=15.1 Hz, 2H), 1.71 (d, J=12.8 Hz,1H), 1.42-1.34 (m, 1H), 1.29-1.20 (m, 4H), 0.87 (ddd, J=8.6, 4.5, 1.9Hz, 2H), 0.58 (ddq, J=10.4, 5.3, 2.8, 1.9 Hz, 2H); MS (ES+) m/z 581(M+1).

Example 175 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-(3,4-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 173, Step 2-6, andmaking non-critical variations as required to replace(3-chloro-5-(trifluoromethyl)phenyl)methanol in Step 2 with(3,4-dichlorophenyl)methanol, the title compound (0.016 g, 50% yield)was obtained as a colorless solid: MS (ES−) m/z 579 (M−1).

Example 176 Synthesis of3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3-azabicyclo[2.1.1]hexane-4-carboxylicacid

Following the procedure as described in Example 046, Step 2 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with4-((1-(3-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acidtrifluoroacetic acid salt with 2-azabicyclo[2.1.1]hexane-1-carboxylicacid, the title compound was obtained as a colorless solid (0.009 g, 29%yield): ¹H NMR (400 MHz, DMSO-d₆) δ 6.95 (d, J=8.0 Hz, 1H), 6.87 (d,J=10.2 Hz, 1H), 2.71-2.65 (m, 2H), 2.09-1.95 (m, 6H), 1.79-1.55 (m,10H), 0.93 (t, J=7.1 Hz, 1H), 0.89 (d, J=8.6 Hz, 2H), 0.66-0.59 (m, 2H):MS (ES+) m/z 454.2 (M+1).

Example 177 Synthesis of(2S,4R,5S)-1-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluorobenzoyl]-4-fluoro-5-methyl-pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 046, Step 2 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with4-((1-(3-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acidtrifluoroacetic acid salt with2(2S,4R,5S)-4-fluoro-5-methylpyrrolidine-2-carboxylic acidtrifluoroacetic acid, the title compound was obtained as a colorlesssolid: ¹H NMR (400 MHz, DMSO-d₆) δ 6.95-6.65 (m, 3H), 5.04 (d, J=3.6 Hz,1H), 4.91 (d, J=3.6 Hz, 1H), 4.44 (t, 0.1=8.9 Hz, 1H), 4.37-4.22 (m,1H), 4.05 (s, 1H), 3.77 (dd, J=19.2, 7.3 Hz, 1H), 3.58 (d, J=18.7 Hz,2H), 2.35-2.12 (m, 1H), 2.09-1.93 (m, 4H), 1.80-1.60 (m, 10H), 1.20 (d,J=6.9 Hz, 1H), 0.99-0.81 (m, 2H), 0.57 (dq, J=7.7, 4.6 Hz, 2H); MS (ES+)m/z 474.2 (M+1).

Example 178 Synthesis of(2R)-3-[4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl]-3-azabicyclo[2.1.1]hexane-2-carboxylicacid

Following the procedure as described in Example 046, Step 2 and makingnon-critical variations as required to replace4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoyl chloride with4-((1-(3-chloro-5-(trifluoroethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride and (2S,4S)-4-hydroxypyrrolidine-2-carboxylic acidtrifluoroacetic acid salt with(S)-2-azabicyclo[2.1.1]hexane-3-carboxylic acid trifluoroacetic acid,the title compound was obtained to as a colorless solid: ¹H NMR (400MHz, DMSO-d₆) δ 6.91-6.80 (m, 2H), 4.30 (s, 1H), 4.01-3.91 (m, 1H),3.65-3.52 (m, 2H), 2.08-1.95 (m, 4H), 1.93-1.84 (m, 1H), 1.77-1.60 (m,1H), 1.45 (dt, J=10.4, 5.4 Hz, 1H), 0.95-0.80 (m, 2H), 0.65-0.52 (m,2H); MS (ES+) m/z 454.2 (M+1).

Example 179 Synthesisof(S)-1-(4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of (S)-tert-butyl(4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace4-((adamantan-1-yl)methoxy)-5-cyclopropropyl-2-fluorobenzoic acid with4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride with(S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride, the titlecompound was obtained as a colorless syrup (0.091 g, 20% yield): ¹H NMR(300 MHz, CDCl₃) δ 8.16-8.12 (m, 1H), 7.78-7.75 (m, 1H), 7.54-7.48 (m,1H), 7.44-7.31 (m, 2H), 6.94-6.89 (m, 1H), 6.58-6.53 (m, 1H), 5.32-5.19(m, 1H), 4.50 (dd, J=4.6, 8.3 Hz, 0.7H), 4.28 (dd, J=2.8, 8.4 Hz, 0.3H),3.91-3.47 (m, 5H), 2.32-2.20 (m, 1.3H), 2.05-1.85 (m, 2.7H), 1.46 (s,6H), 1.36 (d, J=6.2 Hz, 6H), 1.26 (s, 3H) (2:1 mix of rotamers); MS(ES+) m/z 586.1, 588.1 (M+1).

Step 2. Preparation of(S)-1-(4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl(4-((5-chloro-6-isopropoxypyridin-3-yl)oxy)-2-fluoro-5-(2-methoxypyridin-3-yl)benzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.09 g, 75%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.22 (dd, J=1.7, 5.2 Hz, 1H), 7.80 (d,J=2.6 Hz, 1H), 7.62 (dd, J=1.8, 7.3 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H),7.37 (d, J=2.6 Hz, 1H), 7.01 (dd, J=5.2, 7.2 Hz, 1H), 6.58 (d, J=10.8Hz, 1H), 6.11 (br s, 3H), 5.31-5.23 (m, 1H), 4.74 (dd, J=4.4, 8.2 Hz,1H), 3.91 (s, 3H), 3.59-3.55 (m, 2H), 2.44-2.18 (m, 2H), 2.10-1.90 (m,2H), 1.38 (d, J=6.2 Hz, 6H); MS (ES+) m/z 529.9, 531.9 (M+1).

Example 180 Synthesis of(S)-1-(5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of (S-tert-butyl1-(5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoro-propoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzyl)pyrrolidine-2-carboxylate

To a solution of5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid (0.15 g, 0.34 mmol) in anhydrous acetonitrile (8 mL) were addedO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(0.34 g, 1.1 mmol), hydroxybenzotriazole (0.090 g, 0.67 mmol),N,N-diisoprypylethylamine (0.29 mL, 1.7 mmol), and (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride (0.14 g, 0.68 mmol). Thesolution was stirred at ambient temperature for 17 h, then diluted withethyl acetate (100 mL) and washed with 1 M hydrochloric acid (2×100 mL)and brine (2×100 mL). The organic layer was dried over anhydrousmagnesium sulfate, filtered, and concentrated in vacuo. The residue waspurified by column chromatography eluting with a 0-30% gradient of ethylacetate in hexanes to afford the title compound as a colorless syrup(0.14 g, 67% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.76-7.74 (m, 1H), 7.49(d, J=5.8 Hz, 0.7H), 7.42-7.24 (m, 2.3H), 6.05 (t, J=4.9, 53.1 Hz, 1H),5.10-5.08 (m, 2H), 4.73-4.65 (m, 2H), 4.50 (dd, J=4.2, 8.3 Hz, 0.7H),4.14-4.11 (m, 0.3H), 3.83-3.68 (m, 0.6H), 3.54-3.46 (m, 0.7H), 3.42-3.34(m, 0.7H), 2.32-2.23 (m, 1H), 2.06-1.85 (m, 3H), 1.47 (s, 6H), 1.29 (s,3H) (2:1 mix of rotamers); MS (ES+) m/z: 599.0, 601.0 (M+1).

Step 2. Preparation of(S)-1-(5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.12 g, 80%): ¹HNMR (300 MHz, CDCl₃) δ 7.77 (d, J=2.7 Hz, 1H), 7.52 (d, J=5.8 Hz, 1H),7.43 (d, J=2.7 Hz, 1H), 7.35 (d, J=9.7 Hz, 1H), 6.06 (tt, J=4.9, 4.9,53.1, 53.1 Hz, 1H), 5.68 (br s, 2H), 5.11 (s, 2H), 4.74-4.66 (m, 3H),3.51-3.44 (m, 2H), 2.34-2.26 (m, 2H), 2.13-1.88 (m, 2H); MS (ES+) m/z543.0, 544.9 (M+1).

Example 181 Synthesisof(S)-1-(4-((1-(5-chloro-2-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of(S)-tert-butyl1-(4-((1-(5-chloro-2-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 180, Step 1 and makingnon-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with4-((1-(5-chloro-2-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a colorless syrup (0.15 g, 23%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.78 (s, 1H), 7.45-7.38 (m, 2H), 6.91(d, J=7.8 Hz, 0.7H), 6.84 (d, J=7.9 Hz, 0.3H), 6.52-6.45 (m, 1H), 4.46(dd, J=5.1, 8.3 Hz, 0.7H), 4.21-4.18 (m, 0.3H), 3.84-3.70 (m, 3H), 3.64(s, 2H), 3.55-3.47 (m, 0.7H), 3.41-3.32 (m, 0.7H), 3.12-3.04 (m, 0.6H),2.94-2.90 (m, 2H), 2.30-2.13 (m, 3H), 1.99-1.81 (m, 8H), 1.46 (s, 6H),1.25 (s, 3H), 0.88-0.79 (m, 2H), 0.61-0.53 (m, 2H) (2:1 mix ofrotamers): MS (ES+) m/z 639.1, 641.1 (M+1).

Step 2. Preparation of(S)-1-(4-((1-(5-chloro-2-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-((1-(5-chloro-2-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatethe title compound was obtained following purification by reverse-phaseHPLC as colorless solid (0.098 g, 59% yield): ¹H NMR (300 MHz, CDCl₃) δ12.11 (br s, 1H), 8.01 (s, 1H), 7.66-7.58 (m, 2H), 6.89 (d, J=7.4 Hz,1H), 6.46 (d, J=11.5 Hz 1H), 4.84-4.65 (m, 4H), 4.50 (s, 2H), 3.86-3.73(m, 4H), 3.46-3.42 (m, 2H), 2.94-2.85 (m, 2H), 2.41-2.33 (m, 1H),2.25-1.83 (m, 7H), 0.88-0.82 (m, 2H), 0.55-0.50 (m, 2H); MS (ES+) m/z583.1, 585.1 (M+1).

Example 182 Synthesis of(S)-1-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of (S)-tert-butyl(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 180, Step 1 and makingnon-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with4-((3-chloro-5-(trifluoromethoxy)-phenoxy)methyl)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a colorless syrup (0.16 g, 57%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.18-7.09 (m, 2H), 6.91-6.86 (m, 2H),6.73 (br s, 1H), 5.19 (s, 2H), 4.50 (dd, J=4.7 Hz, 8.5 Hz, 0.7H), 4.17(dd, J=2.6, 8.5 Hz, 0.3H), 3.81-3.71 (m, 0.6H), 3.54-3.46 (m, 0.7H),3.40-3.33 (m, 0.7H), 2.34-2.22 (m, 1H), 2.01-1.77 (m, 4H), 1.48 (s, 6H),1.24 (s, 3H), 0.97-0.88 (m, 2H), 0.70-0.64 (m, 2H) (2:1 mix ofrotamers): MS (ES+) m/z 558.1, 560.0 (M+1).

Step 2. Preparation of(S)-1-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl(4-((3-chloro-5-(trifluoromethoxy)-phenoxy)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.077 g, 94%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.24 (s, 1H), 7.20-7.17 (m, 1H),6.92-6.88 (m, 2H), 6.73 (br s, 1H), 6.24 (br s, 1H), 5.21 (s, 2H), 4.73(dd, J=4.1, 8.3 Hz, 1H), 3.48-3.44 (m, 2H), 2.44-2.35 (m, 1H), 2.29-2.17(m, 1H), 2.07-1.78 (m, 3H), 1.01-0.94 (m, 2H), 0.72-0.67 (m, 2H); MS(ES+) ml/501.9, 503.8 (M+1).

Example 183 Synthesis of(S)-2-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzamido)-3-methylbutanoicacid Step 1. Preparation of (S)-tert-butyl2-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzamido)-3-methylbutanoate

Following the procedure as described in Example 180, Step 1 and makingnon-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with4-((3-chloro-5-(trifluoromethoxy)-phenoxy)methyl)-5-cyclopropyl-2-fluorobenzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withtert-butyl L-valinate hydrochloride, the title compound was obtained asa colorless syrup (0.18 g, 74% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.68(d, J=7.7 Hz, 1H), 7.24-7.18 (m, 2H), 6.91-6.87 (m, 2H), 6.74 (s, 1H),5.22 (s, 2H), 4.69-4.64 (m, 1H), 2.31-2.21 (m, 1H), 1.86-1.76 (m, 1H),1.47 (s, 9H), 1.00-0.95 (m, 8H), 0.75-0.70 (m, 2H); MS (ES+) m/z 560.1,562.1 (M+1).

Step 2. Preparation of(S)-2-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzamido)-3-methylbutanoicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl2-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzamido)-3-methylbutanoate,the title compound was obtained as a colorless solid (0.053 g, 75%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.79 (d, J=7.7 Hz, 1H), 7.23 (d,J=12.5 Hz, 1H), 7.16 (dd, J=8.2, 13.7 Hz, 1H), 6.91-6.88 (m, 2H), 6.74(s, 1H), 5.22 (s, 2H), 4.79-4.74 (m, 1H), 2.41-2.30 (m, 1H), 1.86-1.76(m, 1H), 1.06-0.95 (m, 8H), 0.76-0.71 (m, 2H) (acidic proton notobserved); MS (ES+) m/z 503.9, 505.9 (M+1).

Example 184 Synthesis of(S)-1-(5-cyclopropyl-4-(((5-cyclopropyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

To a degassed mixture of(S)-1-(5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)-pyridin-3-yl)oxy)methyl)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid (0.10 g, 0.18 mmol) in toluene (15 mL) and water (1.5 mL) wereadded cyclopropylboronic acid (0.10 g, 1.2 mmol), tribasic potassiumphosphate (0.12 g, 0.56 mmol), tricyclohexylphosphine tetrafluoroborate(0.019 g, 0.062 mmol), and palladium(II) acetate trimer (0.008 g, 0.036mmol). The mixture was heated to reflux under an argon atmosphere for 10h then cooled to ambient temperature. A further amount ofcyclopropylboronic acid (0.050 g, 0.58 mmol), tribasic potassiumphosphate (0.12 g, 0.56 mmol), tricyclohexylphosphine tetrafluoroborate(0.017 g, 0.055 mmol), and palladium(II) acetate trimer (0.006 g, 0.03mmol) were added and the mixture was heated to reflux under an argonatmosphere for 4 h. After cooling to ambient temperature, the mixturewas diluted with ethyl acetate (100 mL) and washed with saturatedaqueous ammonium chloride (2×100 mL). The organic layer was dried overanhydrous magnesium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by reverse-phase HPLC to afford the title compoundas a colorless solid (0.043 g, 42% yield): ¹H NMR (300 MHz, CDCl₃) δ7.60 (d, J=2.8 Hz, 1H), 7.24-7.15 (m, 2H), 6.88 (d, J=2.7 Hz, 1H), 6.01(tt, J=4.7, 53.2 Hz, 1H), 5.18 (s, 2H), 4.73-4.65 (m, 3H), 3.46-3.42 (m,2H), 2.43-2.37 (m, 1H), 2.26-2.14 (m, 1H), 2.04-1.77 (m, 4H), 1.00-0.94(m, 4H), 0.70-0.62 (m, 4H) (acidic proton not observed): MS (ES+) m/z555.1 (M+1).

Example 185 Synthesis of(S)-2-(5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzamido)-3-methylbutanoicacid Step 1. Preparation of (S)-tert-butyl2-(5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzamido)-3-methylbutanoate

Following the procedure as described in Example 180, Step 1 and makingnon-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzoic acidand (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withtert-butyl L-valinate hydrochloride, the title compound was obtained asa colorless syrup (0.30 g, 81% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.18(d, J=7.8 Hz, 1H), 7.87 (dd, J=0.9, 2.6 Hz, 1H), 7.43 (dd, J=1.0, 2.6Hz, 1H), 7.10 (dd, J=8.6, 12.3 Hz, 1H), 6.54 (d, J=12.3 Hz, 1H),4.66-4.62 (m, 1H), 4.12 (dd, J=0.7, 6.7 Hz, 2H), 2.30-2.06 (m, 2H), 1.46(s, 9H), 1.03 (dd, J=0.7, 6.7 Hz, 6H), 0.96 (t, J=7.1 Hz, 6H); MS (ES+)m/z 529.0, 531.0 (M+1).

Step 2. Preparation of(S)-2-(5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzamido)-3-methylbutanoicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl2-(5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzamido)-3-methylbutanoate,the title compound was obtained as a colorless solid (0.14 g, quant.yield): ¹H NMR (300 MHz, CDCl₃) δ 8.18 (d, J=7.8 Hz, 1H), 7.89-7.88 (m,1H), 7.47 (br s, 1H), 7.45-7.44 (m, 1H), 7.05 (dd, J=8.3, 12.9 Hz, 1H),6.54 (d, J=12.4 Hz, 1H), 4.79-4.74 (m, 1H), 4.13 (d, J=6.6 Hz, 2H),2.39-2.29 (m, 1H), 2.20-2.07 (m, 1H), 1.05-0.99 (m, 12H): MS (ES+) m/z473.0, 474.9 (M+1).

Example 186 Synthesis of(2S,3R)-2-(5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzamido)-3-methylpentanoicacid Step 1. Preparation of (2S,3R)-tert-butyl2-(5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzamido)-3-methylpentanoate

Following the procedure as described in Example 180, Step 1 and makingnon-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzoic acidand (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withtert-butyl L-isoleucinate hydrochloride, the title compound was obtainedas a colorless syrup (0.31 g, 82% yield): ¹H NMR (300 MHz, CDCl₃) δ 8.18(d, J=7.9 Hz, 1H), 7.87 (d, J=2.7 Hz, 1H), 7.42 (d, J=2.7 Hz, 1H), 7.15(dd, J=8.2, 12.5 Hz, 1H), 6.53 (d, J=12.3 Hz, 1H), 4.68 (ddd, J=2.4,4.3, 8.0 Hz, 1H), 4.12 (d, J=6.7 Hz, 2H), 2.20-2.06 (m, 1H), 2.00-1.91(m, 1H), 1.55-1.48 (m, 1H), 1.46 (s, 9H), 1.30-1.15 (m, 1H), 1.03 (d,J=6.7 Hz, 6H), 0.97-0.92 (m, 6H); MS (ES+) m/z 543.1, 545.1 (M+1).

Step 2. Preparation of(2S,3R)-2-(5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzamido)-3-methylpentanoicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (2S,3R)-tert-butyl2-(5-chloro-4-((5-chloro-6-isobutoxypyridin-3-yl)oxy)-2-fluorobenzamido)-3-methylpentanoate,the title compound was obtained as a colorless solid (0.12 g, 95%yield): ¹H NMR (300 MHz, CDCl₃) δ 8.18 (d, J=7.9 Hz, 1H), 8.05 (br s,1H), 7.88 (d, J=2.7 Hz, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.08 (dd, J=8.1,13.0 Hz, 1H), 6.54 (d, J=12.4 Hz, 1H), 4.83-4.78 (m, 1H), 4.12 (d, J=6.7Hz, 2H), 2.20-2.02 (m, 2H), 1.61-1.48 (m, 1H), 1.33-1.18 (m, 1H),1.05-0.93 (m, 12H): MS (ES+) m/z 487.0, 489.0 (M+1).

Example 187 Synthesis of(S)-2-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluoro-N-methylbenzamido)-3-methylbutanoicacid Step 1. Preparation of(S)-tert-butyl2-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluoro-N-methylbenzamido)-3-methylbutanoate

To a 0° C. solution of (S)-tert-butyl2-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzamido)-3-methylbutanoate(0.094 g, 0.17 mmol) in anhydrous N,N-dimethylformamide (4 mL) was addedsodium hydride as a 60% dispersion in mineral oil (0.016 g, 0.40 mmol).The mixture was stirred at 0° C. for 1 h. To this mixture was addediodomethane (0.04 mL, 0.6 mmol). The mixture was stirred for 3 h whilewarming to ambient temperature and was then diluted with diethyl ether(75 mL), washed with 1 M hydrochloric acid (100 mL) and brine (2×75 mL),dried over anhydrous magnesium sulfate, and filtered. The filtrate wasconcentrated in vacuo and the residue was purified by columnchromatography, eluting with a 0-2(0% gradient of ethyl acetate inhexanes to afford the title compound as a colorless syrup (0.062 g, 65%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.20-7.14 (m, 1H), 7.08 (d, J=6.5 Hz,0.5H), 7.02-7.01 (m, 0.5H), 6.93-6.90 (m, 1H), 6.87 (br s, 1H),6.74-6.73 (m, 1H), 5.19 (s, 2H), 4.90 (d, J=10.5 Hz, 0.5H), 3.54 (d,J=10.5 Hz 0.5H), 3.08 (s, 1.5H), 2.85 (s, 1.5H), 2.30-2.16 (m, 1H),1.89-1.78 (m, 1H), 1.47 (s, 4.5H), 1.44 (s, 4.5H), 1.07 (d, J=6.5 Hz,2H), 0.97-0.94 (m, 3H), 0.87-0.82 (m, 3H), 0.71-0.66 (m, 2H) (1:1 mix ofrotamers); MS (ES+) m/z 574.1, 576.1 (M+1).

Step 2. Preparation of(S)-2-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluoro-N-methylbenzamido)-3-methylbutanoicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-pyrrolidine-2-carboxylatewith (S)-tert-butyl2-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)-methyl)-5-cyclopropyl-2-fluoro-N-methylbutanoate,the title compound was obtained as a colorless solid (0.057 g, quant.yield): ¹H NMR (300 MHz, CDCl₃) δ 7.22-7.17 (m, 2H), 6.92-6.88 (m, 2H),6.74 (s, 1H), 5.21 (s, 2H), 5.04 (br s, 1H), 4.53-4.50 (m, 1H),2.96-2.95 (m, 3H), 2.52-2.40 (m, 1H), 1.87-1.78 (m, 1H), 1.11 (d, J=6.5Hz, 3H), 1.04 (d, J=6.6 Hz, 3H), 0.99-0.88 (m, 2H), 0.73-0.66 (m, 2H);MS (ES+) m/z 518.0, 520.0 (M+1).

Example 188 Synthesis of(S)-1-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxamide

To a solutionof(S)-1-(4-((3-chloro-5-(trifluoromethoxy)phenoxy)methyl)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid (0.36 g, 0.72 mmol) in anhydrous tetrahydrofuran (12 mL) was added1,1′-carbonyldiimidazole (0.58 g, 3.6 mmol). The solution was heated toreflux under a nitrogen atmosphere for 40 minutes then cooled to ambienttemperature. To this solution was added 30% aqueous ammonium hydroxide(3 mL) that was then stirred at ambient temperature for 5 h. Thesolution was diluted with ethyl acetate (100 mL), washed with 1 Mhydrochloric acid (2×100 mL), brine (100 mL), dried over anhydrousmagnesium sulfate, and filtered. The filtrate was concentrated in vacuoto afford the title compound as a colorless solid (0.35 g, 95% yield):¹H NMR (300 MHz, CDCl₃) δ 7.22-7.13 (m, 1H), 6.91-6.88 (m, 3H), 6.73 (brs, 1H), 5.61 (br s, 1H), 5.20 (s, 2H), 4.76 (dd, J=3.8, 7.6 Hz, 1H),3.50-3.42 (m, 1H), 3.38-3.30 (m, 1H), 2.53-2.37 (m, 2H), 2.14-1.99 (m,2H), 1.92-1.78 (m, 2H), 1.00-0.94 (m, 2H), 0.72-0.66 (m, 2H): MS (ES+)m/z 501.0, 503.0 (M+1).

Example 189 Synthesis of(S)-2-(4-((3S,5S,7S)-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3-cyclopropylpropanoicacid

To a solution of4-(adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid (0.26 g,0.76 mmol) in anhydrous tetrahydrofuran (12 mL) was added1,1′-carbonyldiimidazole (0.13 g, 0.83 mmol). The solution was heated toreflux under a nitrogen atmosphere for 40 minutes, then cooled toambient temperature. To this solution was added L-3-cyclopropylalanine(0.12 g, 0.90 mmol) and 1,8-diazabicycloundec-7-ene (0.32 mL, 2.3 mmol).The solution was stirred at ambient temperature for 15 h, then dilutedwith ethyl acetate (100 mL), washed with 1 M hydrochloric acid (2×100mL) and brine (100 mL), dried over anhydrous magnesium sulfate,filtered, and concentrated in vacuo. The residue was purified byreverse-phase HPLC to afford the title compound as a colorless solid(0.16 g, 45% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.56 (d, J=9.1 Hz, 1H),7.39 (dd, J=6.4, 13.9 Hz, 1H), 6.52 (d, J=14.3 Hz, 1H), 5.75 (br s,1.25H), 4.82-4.77 (m, 1H), 3.52 (s, 2H), 2.07-2.02 (m, 4H), 1.89-1.82(m, 1H), 1.78-1.68 (m, 13H), 0.93-0.87 (m, 2H), 0.83-0.74 (m, 1H),0.68-0.63 (m, 2H), 0.55-0.49 (m, 2H), 0.17-0.13 (m, 2H): ¹⁹F NMR (282MHz, CDCl₃) δ −75.8 (s, 0.7F), −113.1 (s, 1F); MS (ES+) m/z 456.1 (M+1).

Example 190 Synthesis of(S)-1-(4-((1-(3-chloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of(S)-tert-butyl1-(4-((1-(3-chloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 180, Step 1 and makingnon-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with4-((1-(3-chloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was obtained as a light yellow syrup (0.25 g,64% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.09 (br s, 1H), 6.96-6.89 (m,2.7H), 6.83 (d, J=7.8 Hz, 0.3H), 6.48 (d, J=11.7 Hz, 0.7H), 6.45 (d,J=11.5 Hz, 0.3H), 4.45 (dd, J=5.1, 8.4 Hz, 0.7H), 4.18 (dd, J=2.5, 8.3Hz, 0.3H), 3.79-3.71 (m, 2.7H), 3.53-3.31 (m, 3.3H), 2.88-2.84 (m, 2H),2.31-2.18 (m, 1H), 2.04-1.79 (m, 9H), 1.47-1.35 (m, 8H), 1.24 (s, 3H),0.86-0.78 (m, 2H), 0.60-0.52 (m, 2H) (2:1 mix of rotamers): MS (ES+) m/z589.2, 591.1 (M+1).

Step 2. Preparationof(S)-1-(4-((1-(3-chloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-butyl1-(4-((1-(3-chloro-5-fluorobenzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylateand following purification by reverse-phase HPLC, the title compound wasobtained as a colorless solid (0.14 g, 50% yield): ¹H NMR (300 MHz,CDCl₃) δ 12.37 (br s, 1H), 7.18-7.12 (m, 3H), 6.88 (d, J=7.7 Hz, 1H),6.44 (d, J=11.6 Hz, 1H), 4.65-4.61 (m, 1H), 4.20 (s, 2H), 3.82-3.63 (m,5H), 3.48-3.39 (m, 2H), 2.77-2.69 (m, 2H), 2.34-2.19 (m, 2H), 2.03-1.84(m, 8H), 0.88-0.82 (m, 2H), 0.54-0.49 (m, 2H); ¹⁹F NMR (282 MHz, CDCl₃)δ −75.7 (s, 3F), −108.2 (s, 1F), −113.7 (s, 1F); MS (ES+) m/z 533.0,535.0 (M+1).

Example 191 Synthesis of(S)-1-(5-Chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetate Step 1. Preparation of (S)-tert-Butyl1-(5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)-pyridin-3-yl)oxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 180, Step 1 and makingnon-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid (0.20 g, 0.50 mmol), the title was obtained compound as an oil(0.20 g, 74%): MS (ES+) m/z 553.1 (M+1).

Step 2. Preparationof(S)-1-(5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetate

Following the procedure as described in Example 1, Step 2 and makingvariation as required to replace (S)-tert-butyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylatewith (S)-tert-Butyl1-(5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylate,the title compound was obtained following purification by reverse-phaseHPLC as colorless solid (0.070 g, 31%): ¹H NMR (300 MHz, DMSO-d₆) δ8.14-7.99 (m, 2H), 7.61-7.52 (m, 1H), 7.23-6.88 (m, 1H), 7.17-7.08 (m,1H), 5.11-4.96 (m, 2H), 4.65-3.94 (m, 1H), 4.38-4.17 (m, 1H), 3.58-3.29(m, 2H), 2.32-2.16 (m, 1H), 1.99-1.74 (m, 3H); MS (ES+) m/z 499.0, 497.0(M+1).

Example 192 Synthesis of(S)-1-(4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetate

Following the procedure as described in Example 180, Step 1 and 2, andmaking non-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with4-(2-(3-aminobenzo[d]isoxazol-5-yl)-4-chlorophenoxy)-2,5-difluorobenzoicacid, the title compound was obtained following purification byreverse-phase HPLC as colorless solid (0.079 g, 25%): ¹H NMR (300 MHz,DMSO-d₆) δ 8.02-7.91 (m, 1H), 7.68-7.61 (m, 1H), 7.56 (d, J=2.62 Hz,1H), 7.50-7.39 (m, 2H), 7.38-7.26 (m, 1H), 7.24-7.16 (m, 1H), 7.15-6.87(m, 2H), 6.84-6.09 (m, 3H), 4.34-4.14 (m, 1H), 3.56-3.10 (m, 2H),2.29-2.13 (m, 1H), 2.01-1.71 (m, 3H); MS (ES+) m/z 516.1, 514.1 (M+1).

Example 193 Synthesis of(2S)-1-(5-Cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetate

Following the procedure as described in Example 180, Step 1 and 2, andmaking non-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with5-cyclopropyl-4-((1-((3,5-dichlorophenyl)-(phenyl)methyl)piperidin-4-yl)methoxy)-2-fluorobenzoicacid and following purification of the residue by reverse-phase HPLC,the title compound was obtained as a colorless solid (0.032 g. 21%): ¹HNMR (300 MHz, CDCl₃) δ 7.68-7.55 (m, 4H), 7.51-7.31 (m, 4H), 6.92 (d,J=7.7 Hz, 1H), 6.50 (d, JJ=11.6 Hz, 1H), 4.91-4.77 (br, s, 1H), 4.71(dd, J=7.9, 4.2 Hz, 1H), 3.91-3.82 (m, 2H), 3.68-3.34 (m, 4H), 2.80-2.59(m, 2H), 2.54-2.42 (m, 1H), 2.25-1.82 (m, 9H), 0.92-0.79 (m, 2H),0.62-0.53 (m 2H): MS (ES+) m/z 627.0, 625.1 (M+1).

Example 194 Synthesisof(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetate

Following the procedure as described in Example 180, Step 1 and 2, andmaking non-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with 4-(adamantan-1-ylmethoxy)-5-cyclobutyl-2-fluorobenzoic acidand following purification of the residue by reverse-phase HPLC, thetitle compound was obtained as a colorless solid (0.036 g, 31%): ¹H NMR(300 MHz, DMSO-d₆) δ 7.08-6.94 (m, 1H), 6.85-6.72 (m, 1H), 4.37-4.09 (m,1H), 3.97-3.81 (br, s, 2H), 3.64-3.25 (m, 5H), 2.32-2.14 (m 3H),2.13-1.90 (m, 6H), 1.90-1.55 (m, 16H): MS (ES+) m/z 456.1 (M+1).

Example 195 Synthesisof(S)-1-(1-(1-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-6-fluoro-3-methyl-1H-indazole-5-carbonyl)pyrrolidine-2-carboxylicacid trifluoroacetate

Following the procedure as described in Example 180, Step 1 and 2, andmaking non-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with1-(1-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)piperidin-4-yl)-6-fluoro-3-methyl-1H-indazole-5-carboxylicacid and following purification of the residue by reverse-phase HPLC,the title compound was obtained as a colorless solid (0.057 g, 43%): ¹HNMR (300 MHz, DMSO-d₆) δ 7.80 (d, J=9.1 Hz, 1H), 7.75-7.42 (m, 2H),7.26-7.04 (m, 1H), 4.93-4.76 (m, 1H), 4.51-4.41 (m, 2H), 4.41-4.18 (m,1H), 3.61-3.25 (m, 2H), 3.20-3.04 (m, 2H), 2.44-2.38 (m, 3H), 2.33-1.73(m, 8H); MS (ES+) m/z 556.0, 554.0 (M+1).

Example 196 Synthesis of(2S)-1-(5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetate

Following the procedure as described in Example 180, Step 1 and 2, andmaking non-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with5-cyclopropyl-4-((1-((3,5-dichlorophenyl)-(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoicacid and following purification of the residue by reverse-phase HPLC,the title compound was as a colorless solid (0.064 g, 44%): ¹H NMR (300MHz. DMSO-d₆) δ 7.64 (t, J=1.7 Hz, 1H), 7.54 (m, 2H), 7.49-7.39 (m, 5H),6.90-6.67 (m, 2H), 5.81-5.72 (br s, 1H), 4.35-4.26 (m, 1H), 4.15-4.01(m, 4H), 3.98-3.88 (m, 2H), 3.54-3.43 (m, 1H), 3.33-3.21 (m, 1H),2.31-2.13 (m, 1H), 2.05-1.70 (m, 4H), 1.43 (s, 3H), 0.84-0.73 (m, 2H),0.57-0.44 (m, 2H); MS (ES+) m/z 613.0, 611.1 (M+1).

Example 197 Synthesis of(S)-1-(4-((1-((3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetate

Following the procedure as described in Example 180. Step 1 and 2, andmaking non-critical variations to replace5-chloro-4-(((5-chloro-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)oxy)methyl)-2-fluorobenzoicacid with4-((1-((3-(2-chlorophenyl)-1,2,4-oxadiazol-5-yl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and following purification of the residue by reverse-phase HPLC,the title compound was obtained as a colorless solid (0.052 g, 37%): ¹HNMR (300 MHz, CDCl₃) δ 7.91 (d, J 7.5 Hz, 1H), 7.55 (d, J=7.8 Hz, 1H),7.52-7.35 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.47 (d, J=11.3 Hz, 1H),5.38-4.97 (br, s, 2H), 4.74-4.60 (m, 3H), 3.93-3.68 (m, 4H), 3.50-3.39(m, 2H), 3.21-3.06 (m, 2H), 2.44-1.78 (m, 10H), 0.97-0.78 (m, 2H),0.60-0.48 (m, 2H): MS (ES+) m/z 585.1, 583.1 (M+1).

Example 198 Synthesis of(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-oxopyrrolidine-2-carboxylicacid

To a solution of 4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-benzoylchloride (0.17 g, 0.50 mmol) in dichloromethane (2 mL),(S)-5-oxopyrrolidine-2-carboxylic acid (0.07 g, 0.50 mmol) was addedfollowed by N,N-diisopropylethylamine (0.11 mL, 0.75 mmol). The reactionmixture was stirred at ambient temperature for 16 h. The solventconcentrated in vacuo. The residue was purified by column chromatographyeluting with a gradient 0 to 10% methanol in dichloromethane and 2%acetic acid to afford the title compound as a colorless solid (0.014 g,6%): ¹H NMR (300 MHz, DMSO-d₆) δ 6.93 (d, JJ=8.0 Hz, 1H), 6.83 (d,JJ=12.6 Hz, 1H), 4.69 (dd, J=9.0, 3.5 Hz, 1H), 3.63 (s, 2H), 3.36 (s,1H), 2.61-2.52 (m, 2H), 2.47-2.33 (m, 1H), 2.08-1.93 (m, 5H), 1.85-1.50(m, 12H), 0.94-0.83 (m, 2H), 0.63-0.52 (m 2H); MS (ES+) m/z 456.2 (M+1).

Example 199 Synthesis of1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-N-hydroxypyrrolidine-2-carboxamideStep 1. Preparation of1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-N-hydroxypyrrolidine-2-carboxamide

To a solution of(2S,4R)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid (0.10 g, 0.22 mmol), hydroxylamine hydrochloride salt (0.023 g,0.330 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (0.14 g, 0.44 mmol) and 1-hydroxybenzotriazole (0.044g, 0.330 mmol) in acetonitrile (1.7 mL), was addedN,N-diisopropylethylamine (0.19 mL, 1.1 mmol) and stirred under anitrogen atmosphere at ambient temperature for 16 hours. The reactionmixture was then acidified using aqueous hydrochloric acid (1.0 N, 2 mL)and extracted using dichloromethane (4×20 mL). The organic layers werethen combined and washed with saturated aqueous sodium chloride solution(10 mL), dried over magnesium sulfate, concentrated and purified usingpreparative HPLC. The resulting compound in aqueous solution wasextracted using dichloromethane (3×20 mL) and concentrated in vacuo togive the title compound as a colorless solid (0.014 g, 14%): ¹H NMR (300MHz, DMSO-d₆) δ 10.89-10.32 (m, 1H), 9.39-8.66 (m, 1H), 6.95-6.61 (m,2H), 5.49-5.13 (m, 1H), 4.46-3.93 (m, 1H), 3.83-3.40 (m, 4H), 2.48-1.92(m, 6H), 1.79-1.59 (m, 12H), 0.96-0.83 (m, 2H), 0.66-0.54 (m, 2H); MS(ES+) m/z 475.2 (M+1).

Example 200 Synthesis of(S)-5-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-azaspiro[2.4]heptane-6-carboxylicacid

Following the procedure as described in Example 198, and makingvariations as required to replace (S)-5-oxopyrrolidine-2-carboxylic acidwith (S)-5-azaspiro[2.4]heptane-6-carboxylic acid, the title compoundwas obtained as a colorless solid (0.22 g, 56%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.72-12.42 (s, br, 1H), 6.86-6.67 (m, 2H), 4.51-4.15 (m,1H), 3.59-3.49 (m, 2H), 3.33-3.09 (m, 2H), 2.44-2.13 (m, 1H), 2.03-1.79(m, 5H), 1.76-1.52 (m, 12H), 0.90-0.79 (m, 2H), 0.66-0.40 (m, 6H); MS(ES+) m-: 468.3 (M+1).

Example 201 Synthesis of(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorophenyl)((2S,4R)-4-fluoro-2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)pyrrolin-1-methanone

To a solution of(2S,4R)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid (0.20 g, 0.44 mmol) and dimethylformamide (0.05 mL) indichloromethane (1.7 mL), oxalyl chloride (0.06 mL, 0.65 mmol) wasadded. The reaction solution was stirred at ambient temperature for 30minutes and the solvent was concentrated in vacuo to afford a colorlesssolid. This solid was re-dissolved in 1,2-dimethoxyethane (1.7 mL) andcooled to −50° C. To this solution trimethyl(trifluoromethyl)silane(0.46 mL, 3.1 mmol) was added. The reaction solution was to warm to −30°C. and tetramethylammonium fluoride (0.29 g, 3.1 mmol) was added. Thereaction mixture stirred at ambient temperature for 1 hour and acidifiedwith aqueous hydrochloric acid (1.0 N, 4 mL). The reaction mixture wasextracted with dichloromethane (4×20 mL), washed with a saturatedaqueous solution of sodium chloride (10 mL) and the solvent concentratedin vacuo. The residue was purified by preparative HPLC to give the titlecompound as a colorless solid (0.001 g, 0.4%): ¹H NMR (300 MHz, CDCl₃) δ8.60-8.52 (m, 1H), 7.01 (d, J=8.0 Hz, 1H), 6.53 (d, J=12.2 Hz, 1H),5.25-4.91 (m, 2H), 3.86-3.62 (m, 2H), 3.58-3.47 (m, 2H), 2.71-2.53 (m,2H), 2.14-1.97 (m, 4H), 1.89-1.64 (m, 12H), 0.99-0.86 (m, 2H), 0.70-0.53(m, 2H); MS (ES+) m/z 582.2 (M+1).

Example 202 Synthesis of(1R,2S,5S)-3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylicacid Step 1. Preparation of (1R,2S,5S)-Methyl3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate

Following the procedure as described in Example 198, and makingvariations as required to replace (S)-5-oxopyrrolidine-2-carboxylic acidwith ((1R,2S,5S)-methyl6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate, the title compoundwas obtained as a colorless solid, the title compound was obtained as aclear oil (0.20 g, 83%): MS (ES+) m/z 496.3 (M+1).

Step 2. Preparation of(1R,2S,5S)-3-(4-(Adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylicacid

Following the procedure as described in Example 6, Step 2 and makingvariation as required to replace ethyl1-(4-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzaamido)-cyclopropanecarboxylatewith (1R,2S,5S)-methyl3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate,the title compound was obtained following purification using columnchromatography eluting with gradient 5 to 30% of ethyl acetate inhexanes) as a colorless solid (0.007 g, 19%): ¹H NMR (300 MHz, CDCl₃) δ6.89-6.76 (m, 1H), 6.49 (d, J=11.8 Hz, 1H), 4.50 (s, 1H), 3.81-3.68 (m,1H), 3.50-3.43 (m, 2H), 3.30 (d, J=10.9 Hz, 1H), 2.86 (s, 1H), 2.06-1.95(m, 4H), 1.83-1.63 (m, 13H), 1.41-1.30 (m, 1H), 1.09-0.93 (m, 6H),0.90-0.84 (m, 2H), 0.65-0.55 (m, 2H); MS (ES+) m/z 482.3 (M+1).

Example 203 Synthesis of(S)-1-(4-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-2-carboxylicacid Step 1. Preparation of (2S)-Methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate

To a solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicacid (0.072 g, 0.200 mmol) in dichloromethane (2 mL) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.071 g, 0.360 mmol),4-dimethylaminopyridine (0.061 g, 0.500 mmol) and (2S)-methyl4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate (0.041 g, 0.240mmol). After stirring at ambient temperature for 16 h, the reactionmixture was acidified using aqueous hydrochloric acid (1.0 N, 5 mL) andextracted using dichloromethane (4×20 mL). The organic layers were thencombined and washed with saturated aqueous sodium chloride solution (10mL), dried over magnesium sulfate, concentrated in vacuo. The residuewas purified by column chromatography eluting with ethyl acetate inhexanes to afford the title compound as a clear oil (0.83 g, 75%): MS(ES+) m/z 540.2 (M+1).

Step 2. Preparation of (S)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-2-carboxylate

To a solution of (2S)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylatein pyridine (3 mL), was added thionyl chloride (0.32 mL, 4.4 mmol) andstirred under a nitrogen atmosphere at 80° C. for 1 hour. The reactionmixture was then diluted with ether (20 mL) and washed with aqueoushydrochloric acid (1.0 N, 3×20 mL). The organic layers were thencombined and washed with saturated aqueous sodium chloride solution (20mL), concentrated in vacuo. The residue was purified by columnchromatography eluting with ethyl acetate in hexanes to afford the titlecompound as oil (0.070 g, 25%): MS (ES+) m/z 522.3 (M+1).

Step 3. Preparation of(S)-1-(4-adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-2-carboxylicacid

Following the procedure as described in Example 12, Step 2 and makingvariations as required to replace (I R,2S,5S)-methyl3-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylatewith (S)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-(trifluoromethyl)-2,5-dihydro-1H-pyrrole-2-carboxylateand aqueous hydrochloric acid with saturated aqueous ammonium chloridesolution. The residue was purified using preparative HPLC to afford thetitle compound as a colorless solid (0.003 g, 4%): ¹H NMR (300 MHz.DMSO-d₆) δ 7.35-6.82 (m, 2H), 6.55 (s, 1H), 5.97 (s, 1H), 4.27-3.84 (m,3H), 3.67-3.56 (m, 2H), 2.10-1.92 (m, 4H), 1.81-1.57 (m, 12H), 0.97-0.82(m, 2H), 0.68-0.54 (m, 2H); MS (ES+) m/z 508.3 (M+1).

Example 204 Synthesis of(2S,4R)-1-(4-(adamantan-1-ylmethoxy)-2-cyclopropyl-6-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of tert-butyl 2-chloro-4,6-difluorobenzoate

To a solution of 2-chloro-4,6-difluorobenzoic acid (3.00 g, 15.7 mmol)in tetrahydrofuran (30 mL) was added di-tert-butyl dicarbonate (3.77 g,17.3 mmol) and N,N-dimethylaminopyridine (0.38 g, 3.1 mmol) and thereaction mixture was stirred at reflux for 18 hours. The reaction wascooled to ambient temperature, concentrated and aqueous hydrochloricacid (0.25 M, 40 mL) was added and the mixture was extracted withdiethyl ether (3×50 mL). The organic layers were washed with aqueoussodium hydroxide (2N, 15 mL) and brine (30 mL) and then dried overanhydrous magnesium sulfate, filtered and concentrated to give the titlecompound as an oil (3.9 g, 100%).

Step 2. Preparation of tert-butyl4-((adamantan-1-yl)methoxy)-2-chloro-6-fluorobenzoate

A mixture of tert-butyl 2-chloro-4,6-difluorobenzoate (0.49 g, 2.0mmol), 1-adamantyl methanol (0.33 g, 2.0 mmol) with cesium carbonate(2.1 g, 4.0 mmol) in dimethyl sulfoxide (6 mL) was stirred at 70° C. for2 h. The reaction was cooled down to ambient temperature and quenched byaddition of water (10 mL). The reaction mixture was extracted with ethylacetate (3×15 mL), washed with brine (15 mL) and concentrated in vacuo.The residue was purified by chromatography eluting with ethyl acetate inhexanes to afford the title compound as colorless solid (0.61 g, 78%):MS (ES+) m/z 339.1 (M−56+1).

Step 3. Preparation of tert-butyl4-((adamantan-1-yl)methoxy)-2-cyclopropyl-6-fluorobenzoate

A mixture of tert-butyl4-((adamantan-1-yl)methoxy)-2-chloro-6-fluorobenzoate (1.15 g, 2.92mmol), cyclopropyl boronic acid (0.37 g, 4.3 mmol), added palladium(II)acetate (0.1 g, 0.3 mmol), tricyclohexylphosphine tetrafluoroborate(0.21 g, 0.58 mmol), potassium phosphate (1.2 g, 5.8 mmol) and water (2mL) in toluene (6 mL) was degassed and flushed with nitrogen for 10minutes. The reaction mixture was heated at 150° C. in the microwave for90 minutes. The mixture was filtered over diatomaceous earth. Thefiltrate was concentrated in vacuo and the residue was purified bychromatography eluting with ethyl acetate in hexanes to afford the titlecompound as a colorless oil (1.14 g, 98%): ¹H NMR (300 MHz, CDCl₃) δ6.39 (dd, J=11.6, 2.2 Hz, 1H), 6.28 (d, J=1.7 Hz, 1H), 3.41 (s, 2H),2.03-1.94 (m, 4H), 1.79-1.52 (m, 21H), 0.96-0.86 (m, 2H), 0.71-0.62 (m,2H),

Step 4. Preparation of4-(adamantan-1-ylmethoxy)-2-cyclopropyl-6-fluorobenzoic acid

A mixture of tert-butyl4-((adamantan-1-yl)methoxy)-2-cyclopropyl-6-fluorobenzoate (1.1 g, 2.9mmol) and added trifluoroacetic acid (2 mL) in dichloromethane (4 mL)was stirred at ambient temperature for 2 hours. The solvent wasconcentrated and purified by chromatography eluting with ethyl acetatein hexanes to afford the title compound (0.60 g, 59%): MS (ES−) m/z343.1 (M−1).

Step 5. Preparation of (2S,4R)-methyl1-(4-(adamantan-1-ylmethoxy)-2-cyclopropyl-6-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

Following the procedure as described in Example 191, Step 1 and makingvariations as required to replace5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid with 4-(adamantan-1-ylmethoxy)-2-cyclopropyl-6-fluorobenzoic acidand (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride with(2S,4R)-methyl 4-fluoropyrrolidine-2-carboxylate, the title compound wasobtained as clear oil (0.098 g, 49%): MS (ES+) m/z 474.3 (M+1).

Step 6. Preparation of(2S,4R)-1-(4-(adamantan-1-ylmethoxy)-2-cyclopropyl-6-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith (2S,4R)-methyl1-(4-(adamantan-1-ylmethoxy)-2-cyclopropyl-6-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.004 g, 4%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.93-12.52 (s, br, 1H), 6.65 (td, J=11.4, 2.3Hz, 1H), 6.27-6.16 (m, 1H), 5.37-5.14 (m, 1H), 4.45 (dd, J=16.3, 8.1 Hz,1H), 3.67-3.55 (m, 1H), 3.54-3.46 (m, 2H), 3.46-3.33 (m, 1H), 2.71-2.55(m, 1H), 2.29-2.01 (m, 2H), 1.99-1.89 (m, 3H), 1.74-1.52 (m, 12H),0.96-0.64 (m, 4H); MS (ES+m/z 460.2 (M+1).

Example 205 Synthesis of(2S,4R)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-3-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic pivalicanhydride

To a solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicacid (2.78 g, 8.07 mmol) in dichloromethane (32 mL), was addedtriethylamine (1.4 mL, 9.68 mmol) and pivaloyl chloride (1.0 mL, 8.5mmol) at 0° C. and stirred at ambient temperature for 1 hour. Thereaction mixture was then acidified with aqueous hydrochloric acid (1.0N, 20 mL) and extracted with dichloromethane (4×20 mL). The organiclayers were combined and washed with saturated aqueous sodium chloridesolution (10 mL), dried over magnesium sulfate, filtered andconcentrated in vacuo to afford the title compound as yellow solid (3.25g, 94%) that was used directly in the next step.

Step 2. Preparation of (2S,4R)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate

To a solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicpivalic anhydride (1.1 g, 2.6 mmol) in dichloromethane (10 mL),triethylamine (1.80 mL, 12.8 mmol) and (2S,4R)-methyl4-hydroxy-3-methylpyrrolidine-2-carboxylate trifluoroacetic acid salt(0.70 g, 2.56 mmol) were added. The reaction solution was stirred atambient temperature for 16 hours. The reaction mixture was acidifiedwith aqueous hydrochloric acid (1 N, 10 mL) and extracted withdichloromethane (4×20 mL). The combined organic layers were washed withsaturated aqueous sodium chloride solution and concentrated in vacuo.The residue was purified by column chromatography eluting with ethylacetate in hexanes to afford the title compound as clear oil (0.060 g,5%): MS (ES+) m/z 486.3 (M+1).

Step 3. Preparation of (2S,4R)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-3-methylpyrrolidine-2-carboxylate

To a solution of (2S,4R)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate(0.15 g, 0.31 mmol) in dimethylformamide (1.2 mL), sodium hydride (60%in mineral oil) (0.031 g, 0.77 mmol) was added. The reaction mixture wasstirred at ambient temperature for 45 minutes then methyl iodide (0.08mL, 1.2 mmol) was added and continued stirring for 16 hours. Thereaction was quenched with saturated aqueous ammonium chloride (2 mL),extracted with ethyl acetate (4×20 mL) and the solvent was concentratedto afford the title compound as clear oil (0.15 g, 100%), which was useddirectly in the next step.

Step 4. Preparation of(2S,4R)-1-(4-(Adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-3-methylpyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith (2S,4R)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-3-methylpyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.004 g, 4%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.57 (s, 1H), 6.93-6.62 (m, 2H), 3.98 (d,J=7.5 Hz, 1H), 3.93-3.82 (m, 1H), 3.75-3.46 (m, 4H), 3.39-3.27 (m, 1H),3.20 (d, J=2.0 Hz, 3H), 2.07-1.90 (m, 4H), 1.82-1.54 (m, 12H), 1.18-0.99(m, 3H), 0.94-0.83 (m, 2H), 0.65-0.48 (m, 2H); MS (ES+) m/z 486.2 (M+1).

Example 206 Synthesis of2-((S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)pyrrolidin-2-yl)aceticacid

Following the procedure as described in Example 198, and makingvariations as required to replace (S)-5-oxopyrrolidine-2-carboxylic acidwith (S)-2-(pyrrolidin-2-yl)acetic acid, hydrochloride salt and ratherstirring the initial oxalyl chloride reaction mixture for 16 hours. Thereaction mixture was then purified using preparative HPLC to give thetitle compound as a colorless solid (0.070 g, 30%): ¹H NMR (300 MHz,DMSO-d₆) δ 12.26 (s, 1H), 6.89-6.78 (m, 2H), 4.31-3.86 (m, 1H), 3.58 (s,2H), 3.31-3.09 (m, 2H), 2.90 (dd, J=15.7, 3.2 Hz, 1H), 2.34 (dd, J=15.6,9.8 Hz, 1H), 2.05-1.94 (m, 4H), 1.92-1.58 (m, 16H), 0.91-0.83 (m, 2H),0.64-0.56 (m, 2H); MS (ES+) m/z 456.2 (M+1).

Example 207 Synthesis of(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-3-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of (2S,3R,4S)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-3-methylpyrrolidine-2-carboxylate

Following the procedure as described in Example 191, Step 1 and makingvariations as required to replace of5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid with (2S,3R,4S)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylateand (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride with methyl(2S,3R,4S)-4-methoxy-3-methylpyrrolidine-2-carboxylate trifluoroacetate,the title compound was obtained as a clear oil (0.040 g, 40%): MS (ES+)m/z 500.3 (M+1).

Step 2. Preparation of(2S,3R,4S)-1-(4-(Adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-3-methylpyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith (2S,3R,4S)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-3-methylpyrrolidine-2-carboxylateand following the residue purified by column chromatography eluting witha gradient 20 to 40% of ethyl acetate containing 0.5% of formic acid inhexanes, the title compound was obtained as a colorless solid (0.050 g,100%): ¹H NMR (300 MHz, DMSO-d₆) δ 12.63 (s, 1H), 6.92-6.71 (m, 2H),4.01-3.85 (m, 1H), 3.74-3.46 (m, 5H), 3.24-3.12 (m, 4H), 2.09-1.92 (m,4H), 1.79-1.56 (m, 12H), 1.18-0.98 (m, 3H), 0.94-0.82 (m, 2H), 0.65-0.47(m, 2H), MS (ES+) m/z 486.3 (M+1).

Example 208 Synthesis of(2S,4S)-1-(5-Cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of (2S,4S)-methyl1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate

To a solution of (2S)-methyl1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-3-methyl-4-oxopyrrolidine-2-carboxylate(0.710 g, 1.16 mmol) and(S)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (1.4mL, 1.4 mmol) in tetrahydrofuran (5 mL), borane dimethylsulfide complex(0.13 mL, 1.4 mmol) slowly was added at −78° C. The reaction mixture wasstirred at −78° C. for 30 minutes then warmed to ambient temperatureover 1 h and continued stirring for another 30 minutes. The reaction wasquenched with methanol and stirred for 16 h. The reaction mixture wasdiluted with ethyl acetate (5 mL), acidified with saturated aqueousammonium chloride (5 mL) and extracted with ethyl acetate (4×20 mL). Thecombined organic layers were washed with saturated aqueous sodiumchloride solution (10 mL) and the solvent was concentrated in vacuo. Theresidue was purified column chromatography eluting with a gradient 0 to5% of methanol in dichloromethane with 0.5%/0 formic acid to afford thetitle compound as a clear oil (0.25 g, 35%): MS (ES+) m/z 625.2 (M+1).

Step 2. Preparation of2S,4S)-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith (2S,4S)-methyl1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.003 g, 8%): ¹HNMR (300 MHz, DMSO d) δ 12.56 (s, 1H), 7.77 (s, 1H), 7.66 (s, 2H), 6.97(d, J=12.0 Hz, 1H), 6.89-6.73 (m, 1H), 4.70-4.55 (m, 1H), 4.28-4.17 (m,2H), 3.87 (d, J=9.0 Hz, 2H), 3.29-2.95 (m, 6H), 2.38-2.10 (m, 4H),2.05-1.86 (m, 3H), 1.76-1.58 (m, 3H), 1.16-0.99 (m, 3H), 0.92-0.81 (m,2H), 0.65-0.53 (m, 2H); MS (ES+) m/z 611.3, 613.3 (M+1).

Example 209 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of (2S,4R)-methyl1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylate

To a solution of (2S,4S)-methyl1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate(0.030 g, 0.047 mmol) in dichloromethane (0.2 mL),N,N-diethylaminosulfur trifluoride (0.03 mL, 0.19 mmol) and hydrofluoricacid in pyridine (70%, 0.005 mL, 0.190 mmol) were added. The reactionmixture was stirred at 0° C. for 10 minutes then warmed to ambienttemperature and continued stirring for another 30 minutes. The reactionwas quenched with sodium bicarbonate (2 mL) and extracted withdichloromethane (4×20 mL), dried over magnesium sulfate and filtered.The solvent was concentrated and the residue was purified by columnchromatography eluting with a gradient from 0 to 20% of a mixturecomposed of 80% ethyl acetate, 10% isopropyl alcohol and 10%triethylamine in hexanes to afford the title compound as a clear oil(0.040 g, 16%): MS (ES+) m/z 627.2 (M+1).

Step 2. Preparation of(2S,4R)-1-(5-cyclopropyl-4-((1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith (2S,4R)-methyl1-(5-cyclopropyl-4-(1-((S)-1-(3,5-dichlorophenyl)ethyl)-4-fluoropiperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.0065 g, 16%): ¹HNMR (300 MHz, DMSO d₆) δ 13.00-12.64 (m, 1H), 7.79-7.70 (m, 1H),7.68-7.58 (m, 2H), 7.00-6.89 (m, 1H), 6.88-6.80 (m, 1H), 4.69-4.55 (m,1H), 4.29-4.11 (m, 2H), 3.94-3.88 (m, 1H), 3.85-3.58 (m, 4H), 3.21-3.13(m, 1H), 3.10-2.93 (m, 2H), 2.41-2.12 (m, 4H), 2.03-1.92 (m 2H),1.73-1.55 (m, 3H), 1.18-1.05 (m 3H), 0.90-0.80 (m, 2H), 0.65-0.53 (m,2H); MS (ES+) m/z 615.2, 613.2 (M+1).

Example 210a and Example 210b Synthesis of(2S,3S,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylicacid and(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylate

To a solution of (2S,4R)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate(0.140 g, 0.289 mmol) in dichloromethane (1.5 mL) was addedN,N-diethylaminosulfur trifluoride (0.185 mg, 1.15 mmol) and stirred atambient temperature for 2 hours. The reaction was then quenched byaddition of a saturated aqueous solution of sodium bicarbonate (2 mL)and the mixture was extracted with dichloromethane (4×10 mL), dried overmagnesium sulfate, filtered. The filtrate was concentrated in vacuo. Theresidue was purified by normal phase column chromatography eluting witha gradient from 0 to 20% of ethyl acetate in hexanes to give the titlecompound: MS (ES+) m/z 488.2 (M+1).

Step 2. Preparation of(2S,3S,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylicacid

To a solution of crude(2S,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylate(0.136 g, 0.280 mmol) in methanol (0.5 mL), tetrahydrofuran (0.5 mL) andwater (0.5 mL) was added lithium hydroxide (0.067 g, 2.8 mmol) and themixture was stirred at ambient temperature for 16 h. The solvents wereconcentrated in vacuo. The residue was filtered to removed any solidparticles and purified by preparative HPLC to afford first eluent of thetitle compound as a colorless solid (0.006 g, 5%): ¹H NMR (300 MHz,DMSO-d₆) δ 13.02-12.14 (s, br, 1H), 6.90-6.65 (m, 2H), 5.23-4.86 (m,1H), 4.42 and 4.10 (rotamers)—(2×d, J=9.6 Hz, 1H), 3.94-3.65 (m, 2H),3.59-3.52 (m, 2H), 2.85-2.56 (m, 1H), 2.07-1.88 (m, 4H), 1.79-1.51 (m,12H), 1.03 and 0.98 (rotamers)—(2×d, J=7.1 Hz, 3H), 0.92-0.79 (m, 2H),0.62-0.48 (m, 2H) and the second eluent of the title compound as acolorless solid (0.002 g, 2%): ¹H NMR (300 MHz, DMSO-d₆) 13.16-12.45 (s,br, 1H), 6.90-6.65 (m, 2H), 5.14-4.74 (m, 1H), 4.17 and 3.79 (rotamers)(d, J=3.0 Hz, 1H), 4.06-3.85 (m, 1H), 3.77-3.60 (m, 1H), 3.56 and 3.54(rotamers) (s, 2H), 2.77-2.54 (m, 1H), 2.09-1.90 (m, 4H), 1.80-1.50 (m,12H), 1.05 and 0.98 (rotamers) (d, J=7.0 Hz, 3H), 0.94-0.79 (m, 2H),0.65-0.43 (m, 2H); MS (ES+) m/z 474.2 (M+1).

Example 211 Synthesis of(2S,4)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,4S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 191, Step 1 and makingvariations as required to replace5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid with 4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acidand (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride with methyl(2S,4S)-4-(trifluoromethyl)pyrrolidine-2-carboxylate hydrochloride, thetitle compound was obtained as a clear oil and used directly in the nextstep.

Step 2. Preparation of(2S,4S)-1-(4-((Adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 210. Step 2, and makingvariations as required to replace(2S,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylatewith methyl(2S,4S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-(trifluoromethyl)pyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.056 g, 19%): ¹HNMR (300 MHz. DMSO-d₆) δ 6.90-6.69 (m, 2H), 4.54-4.24 (m, 1H), 3.74-3.71(m, 1H), 3.54 (s, 2H), 3.49-3.25 (m, 3H), 2.75-2.37 (m, 2H), 2.07-1.82(m, 5H), 1.77-1.54 (m, 11H), 0.91-0.82 (m, 2H), 0.63-0.47 (m, 2H); MS(ES+) m/z 510.2 (M+1).

Example 212 Synthesis of2-(4-((Adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-2-azabicyclo[3.1.0]hexane-1-carboxylicacid

Following the procedure as described in Example 198, and makingvariations as required to replace (S)-5-oxopyrrolidine-2-carboxylic acidwith 2-azabicyclo[3.1.0]hexane-1-carboxylic acid, hydrochloric acidsalt, the title compound was obtained as a colorless solid (0.125 g,37%): ¹H NMR (300 MHz, CDCl₃) δ 7.12-6.84 (m, 1H), 6.59-6.40 (m, 1H),4.19-3.86 (m, 2H), 3.47 (s, 2H), 3.16-2.86 (m, 1H), 2.41-1.92 (m, 8H),1.88-1.58 (m, 13H), 0.96-0.78 (m, 2H), 0.73-0.46 (m, 2H); MS (ES+) m/z454.3 (M+1).

Example 213 Synthesis of(2S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylatehydrochloride

To a solution of(2S)-1-(tert-butoxycarbonyl)-4-hydroxy-4-(trifluoromethyl)-pyrrolidine-2-carboxylicacid (2.55 g, 8.15 mmol) in 1,4-dioxane (10 mL) at 0° C., a solution ofhydrochloric acid in 1,4-dioxane (4N, 3 mL) was added. The reactionmixture was warm up to ambient temperature over 1 hour. The stirring wascontinued for another 4 h at which point a precipitate formed. Theprecipitate was filtered and rinsed with diethyl ether (3×10 mL) anddried in vacuo to afford the title compound (0.45 g, 28%): ¹H NMR (300MHz, CDCl₃) δ 10.50-9.98 (s, br, 2H), 4.72 (dd, J=9.6, 3.3 Hz, 1H), 3.73(s, 3H), 3.45-3.37 (m, 2H), 2.55 (dd, J=14.0, 9.7 Hz, 1H), 2.39 (dd,J=13.7, 3.0 Hz, 1H),

Step 2. Preparation of methyl(2S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate

To a solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoicacid (0.137 g, 0.400 mmol) in dichloromethane (2 mL) and DMF (0.05 mL),was added oxalyl chloride (0.04 mL, 0.50 mmol) and stirred under anitrogen atmosphere at ambient temperature for 30 minutes. The reactionmixture was then concentrated and dried under high vacuum to produce acolorless solid, which was then dissolved in dichloromethane (2 mL).(2S)-4-hydroxy-4-(trifluoro-methyl)pyrrolidine-2-carboxylic acid,hydrochloric acid salt (0.075 g, 0.300 mmol) was then added to thereaction mixture, followed by N,N-diisopropylethylamine (0.26 mL, 0.50mmol) and the reaction mixture was stirred under a nitrogen atmospherefor 30 minutes at ambient temperature. The reaction was then quenched byaddition of a saturated aqueous solution of sodium bicarbonate (10 mL)and the mixture was extracted with dichloromethane (4×10 mL), dried overmagnesium sulfate, filtered. The filtrated was concentrated in vacuo andthe residue was purified by column chromatography eluting with agradient from 0 to 40% of ethyl acetate containing 0.5% of acetic acidin hexanes to afford the title compound which was used directly in thenext step.

Step 3. Preparation of(2S)-1-(4-((Adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(ter-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith (2S)-Methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylateand following the residue was purified by preparative HPLC, the titlecompound was obtained as a colorless solid (0.081 g, 38%): ¹H NMR (300MHz, DMSO-d₆) δ 6.92-6.73 (m, 2H), 4.71-4.24 m, 1H), 3.88-3.61 (m, 1H),3.61-3.45 (m, 3H), 3.12-2.49 (m, 2H), 2.23-2.08 (m, 1H), 2.07-1.89 (m,4H), 1.78-1.53 (m, 12H), 0.92-0.80 (m, 2H), 0.63-0.45 (m, 2H): MS (ES+)m/z 526.3 (M+1).

Example 214 Synthesis of(2S)-1-(4-((Adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate

Following the procedure as described in Example 205, Step 3 and makingnon-critical variations as required to replace (2S,4R)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate(2S)-methyl1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-(trifluoromethyl)pyrrolidine-2-carboxylate,the residue obtained was directly used in the next step.

Step 2. Preparation of(2S)-1-(4-((Adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith(2S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-methoxy-4-(trifluoromethyl)pyrrolidine-2-carboxylateand following the residue purified by preparative HPLC, the titlecompound was obtained as a colorless solid (0.028 g, 14%): ¹H NMR (300MHz, DMSO-d₆) δ 6.92-6.73 (m, 2H), 4.70-4.19 (min, 1H), 3.90-3.63 (m,2H), 3.62-3.50 (m, 2H), 3.26 (s, 4H), 2.70-2.51 (m, 1H), 2.42-2.30 (m1H), 2.07-1.90 (m, 4H), 1.78-1.53 (m, 12H), 0.92-0.80 (m, 2H), 0.63-0.44(m, 2H); MS (ES+) m/z 540.3 (M+1).

Example 215 Synthesis of2-((S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)azetidin-2-yl)aceticacid Step 1. Preparation of tert-butyl(S)-2-(2-diazoacetyl)azetidine-1-carboxylate

To a solution of (S)-1-(tert-butoxycarbonyl)azetidine-2-carboxylic acid(0.57 g, 2.8 mmol) and triethylamine (0.48 mL, 3.4 mmol) intetrahydrofuran (3 mL) at 0° C., isobutyl chloroformate (0.41 mL, 3.1mmol) was added. The reaction mixture was stirred at ambient temperaturefor 1 hour and then filtered through a pad of diatomaceous earth,rinsing with small amounts of acetonitrile (3×5 mL). The filtrate wasconcentrated in vacuo and the re-dissolved in acetonitrile (3 mL) andtrimethylsilyldiazomethane (1.34 mL, 8.47 mmol) was added undernitrogen. The reaction mixture was stirred at ambient temperature for 16hours and quenched by addition of a saturated aqueous solution of sodiumbicarbonate (10 mL). The mixture was extracted with ethyl acetate (2×15mL), washed with brine (20 mL), dried over anhydrous magnesium sulfateand filtered. The filtrate was concentrated in vacuo to afford the titlecompound which was used directly into the next step.

Step 2. Preparation of tert-butyl(S)-2-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate

To a solution of tert-butyl (S)-2-(2-diazoacetyl)azetidine-1-carboxylate(0.64 g, 2.8 mmol) in methanol was added triethylamine (2.0 mL, 14 mmol)followed by silver (I) trifluoroacetate (0.43 mg, 1.7 mmol). Thereaction mixture was stirred at 60° C. for 2 h, then cooled to ambienttemperature and the solvents were concentrated in vacuo. The residue waspurified by flash chromatography eluting with ethyl acetate in hexanesto afford the title compound (0.25 g, 39%): MS (ES+) m/z 230.1 (M+1).

Step 3. Preparation of methyl (S)-2-(azetidin-2-yl)acetate hydrochloride

Tert-butyl (S)-2-(2-methoxy-2-oxoethyl)azetidine-1-carboxylate (0.13 g,0.56 mmol) was dissolved in a solution of hydrochloric acid in1,4-dioxane (4N, 1 mL) and stirred for 1 hour at ambient temperature.The solvent was concentrated in vacuo to afford the title compound: MS(ES+) m/z 130.1 (M+1).

Step 4. Preparation of methyl2-((S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)azetidin-2-yl)acetate

Following the procedure as described in Example 198, and makingvariations as required to replace (S)-5-oxopyrrolidine-2-carboxylic acidwith methyl (S)-2-(azetidin-2-yl)acetate hydrochloride, the titlecompound was obtained as a colorless oil (0.025 g, 14%): MS (ES+) m/z456.2 (M+1).

Step 4. Preparation of2-((S)-1-(4-((Adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)azetidin-2-yl)aceticacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl2-((S)-1-(4-((adamantan-1-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)azetidin-2-yl)acetate,the title compound was obtained as a colorless solid (0.004 g, 16%): ¹HNMR (300 MHz, DMSO-d₆) δ 12.48-12.11 (s, br, 1H), 7.06-6.70 (m, 2H),4.60-4.46 (m, 1H), 4.04-3.67 (m, 2H), 3.55 (s, 2H), 3.00-2.84 (m, 1H),2.75-2.57 (m, 1H), 2.55-2.49 (m, 1H), 2.43-2.30 (m, 1H), 2.05-1.86 (m,4H), 1.74-1.52 (m, 12H), 0.91-0.80 (m, 2H), 0.61-0.51 (m, 2H); MS (ES+)m/z 442.2 (M+1).

Example 216 Synthesis of(4-((1-(3-Chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-L-valine

Following the procedures as described in Example 191. Step 1 and 2 andmaking variations as required to replace of5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid with4-((1-(3-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid and (S)-tert-butyl pyrrolidine-2-carboxylate hydrochloride withtert-butyl L-valinate, the title compound was obtained as a colorlesssolid (0.006, 5%): ¹H NMR (300 MHz, DMSO-d₆) δ 8.03-7.93 (m, 1H),7.78-7.68 (m, 2H), 7.21 (d, J 8.8 Hz, 1H), 6.87 (d, J=13.7 Hz, 1H),4.08-3.99 (m, 1H), 3.92-3.86 (m, 2H), 3.61 (s, 2H), 3.35-3.29 (m, 2H),2.87-2.77 (m, 2H), 2.72-2.55 (m, 2H), 2.14-1.93 (m, 4H), 1.80-1.70 (m,2H), 0.90-0.77 (m, 8H), 0.58-0.51 (m, 2H); MS (ES+) m/z 605.2, 603.2(M+1).

Example 217 Synthesisof(S)-1-(5-Chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoyl)pyrrolidine-2-carboxylicacid trifluoroacetate

Following the procedures as described in Example 191, Step 1 and 2 andmaking variations as required to replace of5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid with5-chloro-4-((5-chloro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)oxy)-2-fluorobenzoicacid, the title compound was obtained as a colorless solid (0.071, 23%):¹H NMR (300 MHz, DMSO-d₆) δ8.14-7.99 (m, 2H), 7.61-7.52 (m, 1H),7.23-6.88 (m, 1H), 7.17-7.08 (m, 1H), 5.11-4.96 (m, 2H), 4.65-3.94 (m,1H), 4.38-4.17 (m, 1H), 3.58-3.29 (m, 2H), 2.32-2.16 (m, 1H), 1.99-1.74(m, 3H): MS (ES+) m/z 499.0, 497.0 (M+1).

Example 218 Synthesis of(2S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of(S)-2-(methoxycarbonyl)-4-oxopyrrolidin-1-ium trifluoroacetate

To a solution of 1-(tert-butyl) 2-methyl(S)-4-oxopyrrolidine-1,2-dicarboxylate (3.00 g, 12.3 mmol) indichloromethane (72 mL) was added trifluoroacetic acid (2.8 mL, 37.0mmol). The reaction mixture was stirred at ambient temperature 2 h,after which it was evaporated in vacuo. The residue was used directlyfor the next step.

Step 2. Preparation of methyl(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-oxopyrrolidine-2-carboxylate

Following the procedure as described in Example 1, Step 1 and makingvariation as required to replace (S)-tert-butylpyrrolidine-2-carboxylate hydrochloride with(S)-2-(methoxycarbonyl)-4-oxopyrrolidin-1-ium trifluoroacetate, thetitle compound was obtained as a colorless solid (1.95 g, 69%): ¹H NMR(300 MHz, CDCl₃) δ 6.95 (d, J=7.5 Hz, 1H), 6.51 (d, J=11.9 Hz, 1H), 5.24(d, J=10.1 Hz, 1H), 4.05-3.95 (m, 1H), 3.79 (s, 3H), 3.65 (s, 1H), 3.49(s, 2H), 3.10-2.92 (m, 1H), 2.75-2.50 (m, 1H), 2.02 (s, 4H), 1.87-1.60(m, 12H), 0.89 (d, J=8.3 Hz, 2H), 0.70-0.55 (m, 2H),

Step 3. Preparation of methyl(2S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-methylpyrrolidine-2-carboxylate

To a cooled (−78° C.) solution of methyl(S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-oxopyrrolidine-2-carboxylate(0.30 g, 0.64 mmol) in tetrahydrofuran (4.5 mL), a solution of methylmagnesium bromide (0.30 mL, 3.0 mol/L in diethyl ether) was addeddropwise under nitrogen atmosphere. The reaction mixture was warmed to−15° C. over 5 h, quenched with the addition of saturated ammoniumchloride (50 mL) and extracted with ethyl acetate (3×50 mL). Thecombined organic layers were dried over anhydrous magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography to afford the title compound as a colorless oil (0.098 g,27%): MS (ES+) m/z 486.3 (M+1).

Step 4. Preparation of(2)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-methylpyrrolidine-2-carboxylicacid

Following the procedure as described in Example 230. Step 2 and makingnon-critical variations as required to replace methyl(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylatewith methyl(2S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-4-methylpyrrolidine-2-carboxylate,the tile compound was obtained as a colorless solid (0.042 g, 44%): ¹HNMR (300 MHz, CDCl₃) δ 7.28-7.22 (m, 1H), 6.49 (d, J=11.7 Hz, 1H), 4.76(m, 1H), 3.48-3.45 (m, 4H), 2.55-2.16 (m, 2H), 2.02 (s, 4H), 1.73-1.67(m, 12H), 1.34 (s, 3H), 0.87 (m, 2H), 0.61 (m, 2H); Note: COOH and OHsignals were not observed; ¹⁹F NMR (282 MHz, CDCl₃) δ −113.9 (s, 1F); MS(ES−) m/z 470.2 (M−1).

Example 219 Synthesis of(2S,3R,4R)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,3R,4R)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylate

A premixed solution of hydrofluoric acid (70% in pyridine, 0.012 mL,0.44 mmol) and diethylaminosulfur trifluoride (0.059 mL, 0.44 mmol) in1,2-dichloroethane was added dropwise to a solution of methyl(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate(0.050 g, 0.10 mmol) in 1,2-dichloroethane (5.0 mL) 0° C. The reactionmixture was warmed to ambient temperature overnight and quenched withthe addition of solid sodium bicarbonate (0.015 g). The heterogeneousmixture was purified by column chromatography to afford the titlecompound as a colorless oil (0.029 g, 58% yield): MS (ES+) m/z 488.3(M+1).

Step 2. Preparation of(2S,3R,4R)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylicacid

Following the procedure as described in Example 229, Step 2 and makingnon-critical variations as required to replace methyl(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylatewith methyl(2S,3R,4R)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoro-3-methylpyrrolidine-2-carboxylate,the title compound was obtained as a colorless solid (0.020 g, 20%yield): ¹H NMR 300 MHz, CDCl₃) δ 7.00 (d, J=6.2 Hz, 1H), 6.51 (d, J=11.8Hz, 1H), 5.78 (br s, 1H), 4.90 (d, J=53.4 Hz, 1H), 4.36 (d, J=10.5 Hz,1H), 3.96-3.60 (m, 2H), 3.49 (s, 2H), 2.71-2.60 (m, 1H), 2.02 (s, 4H),1.81-1.59 (m, 12H), 1.24 (d, J=5.1 Hz, 3H), 0.91 (d, J=7.9 Hz, 2H), 0.61(s, 2H); ¹⁹F NMR (282 MHz, CDCl₃) δ −112.9 (s), −195.9 (s); ¹³C NMR (75MHz, CDCl₃) δ 173.2, 168.2, 161.6, 159.1, 156.2, 129.0, 126.4, 113.1,98.8, 93.4 (d, J=182.3 Hz), 78.8, 64.2, 55.2, 44.7, 39.5, 37.1, 33.9,28.1, 11.2, 9.5, 7.0; MS (ES+) m/z 474.1 (M+1).

Example 220 Synthesis of (2S4R)-1-(4-((1-((5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Synthesis of methyl(2S,4R)-1-(4-((I-((5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)-piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

To a solution of4-((1-((5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid (0.10 g, 0.21 mmol) in acetonitrile (2.5 mL) was addedN,N-diisopropylethylamine (0.18 mL, 1.03 mmol), hydroxybenzotriazole(0.042 g, 0.31 mmol). O-(Benzotriazol-1-yl)-N,N,N′N′-tetramethyluroniumtetrafluoroborate (0.13 g, 0.41 mmol) and trans-4-fluoro-1-prolinemethyl ester (0.08 g, 0.31 mmol). The reaction mixture was stirred atambient temperature overnight, then diluted with saturated sodiumcarbonate, and extracted with ethyl acetate (3×75 mL). The combinedorganic extracts were dried over anhydrous magnesium sulfate, filteredand concentrated in vacuo. The residue was purified by columnchromatography eluting with ethyl acetate in hexanes to afford the titlecompound as yellow oil (0.03 g, 25%): ¹H NMR (300 MHz, CDCl₃) δ 7.92(dd, J=7.5 Hz, 1.8 Hz, 1H), 7.55-7.48 (m, 1H), 7.44-7.33 (m, 2H), 6.60(d. J=8.1 Hz, 1H), 6.49 (d, J=8.1 Hz, 1H), 5.19 (d, J=51.3 Hz, 1H), 4.79(t, J=8.7 Hz, 1H), 3.97 (s, 2H), 3.85-3.62 (m, 6H), 3.15-3.00 (m, 2H),2.75-2.55 (m, 1H), 2.32 (t, J=10.2 Hz, 2H), 2.04-1.77 (m, 5H), 1.61-1.45(m, 2H), 1.23 (t, J=7.2 Hz, 1H), 0.92-0.77 (m, 2H), 0.65-0.52 (m, 2H);MS (ES+) m/z 615.2 (M+1).

Step 2. Synthesis of(2S,4R)-1-(4-((1-((5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

To a solution of methyl(2S,4R)-1-(4-((1-((5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)methyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate(0.032 g, 0.052 mmol) in tetrahydrofuran (1 mL), water (1 mL) andmethanol (0.4 mL) was added potassium carbonate (0.036 g, 0.26 mmol).The reaction was fitted with a condenser and heated at reflux for 2 h.The reaction mixture was diluted with saturated ammonium chloride,extracted with ethyl acetate (3×50 mL), dried over anhydrous magnesiumsulfate, filtered, and evaporated to dryness. The residue was purifiedby preparative HPLC (acetonitrile and water with 0.1% trifluoroaceticacid) to afford the title compound as a colorless solid (0.029 g, 92%):¹H NMR (300 MHz, CDCl₃) δ 7.91 (s, 1H), 7.53-7.35 (m, 3H), 7.28-7.23 (m,1H), 6.99-6.86 (m, 1H), 6.54-6.34 (m, 1H), 5.18 (d, J=53.7 Hz, 1H), 4.81(br s, 1H), 4.43 (s, 2H), 3.75-3.51 (m, 6H), 2.84 (br s, 2H), 2.63-2.35(m, 2H), 1.95-1.78 (m, 6H), 0.83 (br s, 2H), 0.53 (br s, 1H): Note:acidic proton not observed; MS (ES+) m/z 601.2 (M+1).

Example 221 Synthesis of(S)-5-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-azaspiro[2.4]heptane-6-carboxylicacid Step 1. Preparation of (S)-6-carboxy-5-azaspiro[2.4]heptan-5-iumtrifluoroacetate

To a solution of(6S)-5-(tert-butoxycarbonyl)-5-azaspiro[2.4]heptane-6-carboxylic acid(0.40 g, 1.66 mmol) in dichloromethane (20 mL) was added trifluoroaceticacid (3.8 mL, 49.8 mmol). The solution was stirred at ambienttemperature for 2 hours, and then evaporated to dryness in vacuo. Theresidue was used without further purification.

Step 2. Preparation of4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride

To a solution of4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid (0.38 g, 0.76 mmol) in acetonitrile (5.1 mL) was added oxalylchloride (0.98 mL, 11.4 mmol), followed by N,N-dimethylformamide (0.02mL). The reaction mixture was stirred under nitrogen for 2 h, and thenconcentrated in vacuo. The residue was used without further purificationor characterization.

Step 3. Preparation of(S)-5-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxyl)-5-cyclopropyl-2-fluorobenzoyl)-5-azaspiro[2.4]heptane-6-carboxylicacid

To a solution of4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride (obtained from 0.38 g of4-((1-(2-chloro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid) in acetonitrile (2 mL) was added N,N-diisopropylethylamine (1.3mL, 7.6 mmol), followed by (S)-6-carboxy-5-azaspiro[2.4]heptan-5-iumtrifluoroacetate (1.66 mmol). The reaction mixture was stirred atambient temperature for 16 h, after which it was diluted with aqueoushydrochloric acid (1 mol/L, 15 mL). The pooled organic fractions wereextracted with ethyl acetate (3×100 mL), dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedby preparative HPLC (acetonitrile and water with 0.1% trifluoroaceticacid) to afford the title compound as a colorless solid (0.069 g, 15%):¹H NMR (300 MHz, CDCl₃) δ 8.00 (s, 1H), 7.52 (s, 1H), 6.77 (d, J=7.8 Hz,1H), 6.23 (d, J=11.4 Hz, 1H), 4.61 (t, J=7.8 Hz, 1H), 4.15-3.83 (m, 5H),3.56 (d, J=10.2 Hz, 1H), 3.38-3.24 (m, 1H), 3.06-2.95 (m, 1H), 2.90 (d,J=10.2 Hz, 1H), 2.84-2.66 (m, 2H), 2.25-1.84 (m, 7H), 0.90-0.70 (m, 2H),0.63-0.42 (m, 6H); MS (ES+) m/z 625.1 (M−1). Note: acidic proton notobserved.

Example 222 Synthesis of(2S,4R)-1-(5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,4R)-1-(5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate

To a solution of5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoicacid (0.52 g, 0.91 mmol) in dichloromethane (5.5 mL) was addedN,N-dimethylaminopyridine (0.33 g, 2.73 mmol),(2S,4R)-4-fluoro-2-(methoxycarbonyl)pyrrolidin-1-ium chloride (0.50 g,2.73 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (0.53 g, 2.73 mmol). The reaction mixture was stirred atambient temperature for 16 h, and then diluted with saturated ammoniumchloride (50 mL). The solution was extracted with dichloromethane (3×50mL), dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo to afford a residue that was purified by column chromatographyeluting with ethyl acetate in hexanes to afford methyl(2S,4R)-1-(5-cyclopropyl-4-((l-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylateas a white foam (0.23 g, 42%): ¹H NMR (300 MHz, CDCl₃) δ 7.32-7.25 (m,2H), 7.15-7.07 (m, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.48 (d, J=12.0 Hz, 1H),5.20 (d, J=52.2 Hz, 1H), 4.80 (t, J=8.4 Hz, 1H), 3.80-3.70 (m, 7H),3.05-2.90 (m, 2H), 2.75-2.55 (m, 1H), 2.35-2.16 (m, 3H), 2.05-1.68 (m,5H), 1.45-1.20 (m, 3H), 0.90-0.84 (m, 2H), 0.65-0.55 (m, 2H): MS (ES+)m/z 581.2, 583.2 (M+1).

Step 2. Preparation of(2S,4R)-1-(5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(2S,4R)-1-(5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-4-fluoropyrrolidine-2-carboxylate,the title compound was obtained as colorless solid (0.18 g, 82%): ¹H NMR(300 MHz, DMSO-d₆) δ 9.85 (br s, 1H), 7.70-7.45 (m, 3H), 7.11-6.70 (m,2H), 5.25 (d, J=52.8 Hz, 1H), 4.70-4.40 (m, 3H), 4.35-4.05 (m, 1H),3.95-3.80 (m, 2H), 3.75-3.40 (m, 5H), 2.72-2.50 (m, 1H), 2.35-1.95 (m,5H), 1.85-1.65 (m, 2H), 0.92-0.77 (m, 2H), 0.65-50 (m, 2H): MS (ES−) m/z567.0 (M−1), 569.0 (M−1)

Example 223 Synthesis of2-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzamido)-3,3,3-trifluoropropanoicacid

To a solution of 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoylchloride (1.0 mmol) in acetonitrile (7 mL) was addedN,N-diisopropylethylamine (1.7 mL, 10 mmol) and2-amino-3,3,3-trifluoropropanoic acid (0.32 g, 2.2 mmol). The reactionmixture was stirred at ambient temperature overnight, diluted withaqueous hydrochloric acid (1 mol/L, 50 mL), and then extracted withethyl acetate (5×75 mL). The combined organic extracts were dried overanhydrous magnesium sulfate, filtered and concentrated in vacuo toobtain a residue that was purified by column chromatography eluting withethyl acetate in hexanes with 0.2% trifluoroacetic acid, followed bypreparative HPLC (acetonitrile and water with 0.1% trifluoroacetic acid)to afford the title compound as colorless solid (0.52 g, 11%): ¹H NMR(300 MHz, CDCl₃) δ 8.80-8.76 (m, 1H), 7.14 (d, J=9.0 Hz, 1H), 6.87 (d,J=14.0 Hz, 1H), 5.35-5.27 (m, 1H), 3.60 (s, 2H), 2.10-1.95 (m, 4H),1.80-1.55 (m, 12H), 0.95-0.85 (m, 2H), 0.65-0.55 (m, 2H); Note:carboxylic acid (COOH_) proton not observed: MS (ES+) m/z 470.1 (M+1).

Example 224 Synthesis of(4S,5R)-3-(5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid Step 1. Preparation of dimethyl3,3′-methylene(4S,4'S,5R,5′R)-bis(5-methyloxazolidine-4-carboxylate)

To a suspension of L-threonine methyl ester hydrochloride (2.80 g, 16.50mmol) in dichloromethane (100 mL) was added triethylamine (2.75 mL,17.80 mmol) and para-formaldehyde (1.03 g). The solution was stirred atambient temperature for 16 h. The reaction mixture was then evaporatedto dryness in vacuo, and triturated with diethyl ether. The precipitatedsolid was washed with diethyl ether (250 mL), after which the filtratewas evaporated in vacuo. The resulting clear oil was used in the nextwithout further purification or characterization.

Step 2. Preparation of methyl(4S,5R)-3-(5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)-piperidin-4-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate

To a solution of dimethyl3,3′-methylene(4S,4′S,5R,5′R)-bis(5-methyloxazolidine-4-carboxylate)(0.41 g, 1.32 mmol) in acetonitrile (7.0 mL) and saturated sodiumcarbonate (7.0 mL) was dropwise added a solution of4-((4-(chlorocarbonyl)-2-cyclopropyl-5-fluorophenoxy)-methyl)-1-(2,6-dichlorobenzyl)piperidin-1-iumtrifluoroacetate (1.55 g, 2.64 mmol) in acetonitrile (6.0 mL). Thereaction mixture was stirred at ambient temperature for 16 h, afterwhich it was diluted with water and extracted with ethyl acetate (4×75mL). The combined organic extracts were dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography to afford the title compound as a colorless solid(0.48 g, 63%): ¹H NMR (300 MHz, CDCl₃) δ 7.30 (s, 1H), 7.27 (s, 1H),7.18-7.09 (m, 1H), 7.00 (d, J=8.1 Hz, 1H), 6.49 (d, J=12.0 Hz, 1H),4.97-4.88 (m, 1H), 4.44-4.03 (m, 2H), 3.81-3.63 (m, 6H), 3.05-2.87 (m,2H), 2.25 (t, J=11.4 Hz, 2H), 1.85-1.73 (m, 2H), 1.59 (s, 3H), 1.49 (d,J=6.0 Hz, 2H), 1.44-1.20 (m, 4H), 0.87-0.80 (m, 2H), 0.69-0.50 (m, 2H);MS (ES+) m/z 579.0, 581.0 (M+1).

Step 3. Preparation of(4S,5R)-3-(5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(4S,5R)-3-(5-cyclopropyl-4-((1-(2,6-dichlorobenzyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate,the title compound was obtained as colorless solid (0.36 g, 77% yield):¹H NMR (300 MHz, CDCl₃) δ 10.30-9.70 (br s, 1H), 7.65-7.57 (m, 2H),7.55-7.45 (m, 1H), 7.00-6.75 (m, 2H), 4.88-4.72 (m, 2H), 4.49 (s, 2H),4.22-4.05 (m, 2H), 3.97-3.77 (m, 2H), 3.65-3.40 (m, 4H), 2.15-1.70 (m,6H),1.37 (d, J=5.7 Hz, 2H), 1.29 (d, J=4.8 Hz, 1H), 0.85 (d, J=8.1 Hz,2H), 0.65-0.52 (m, 2H): MS (ES+) m/z 565.0, 567.0 (M+1).

Example 225 Preparation of(4S,5R)-3-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid Step 1. Preparation of4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride

To a solution of4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid (0.30 g, 0.60 mmol) in dichloromethane (3.0 mL) was added thionylchloride (3.0 mL). The reaction mixture was stirred at ambienttemperature for 12 h then solvent was concentrated in vacuo and usedwithout further purification or characterization.

Step 2. Preparation of methyl(4S,5R)-3-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate

Following the procedure as described in Example 223. Step 2 and makingnon-critical variations as required to replace4-((4-(chlorocarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-1-(2,6-dichlorobenzyl)piperidin-1-iumtrifluoroacetate with4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride, the title compound was obtained as pale yellow oil (0.22 g,58% yield): MS (ES+) m/z 649.0, 651.0 (M+1)

Step 3. Preparation of(4S,5R)-3-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(4S,5R)-3-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate,the tile compound was obtained as a colorless solid (0.20 g, 86%): ¹HNMR (300 MHz, CDCl₃) δ 11.15 (s, 1H), 8.22 (s, 2H), 7.12-6.80 (m, 2H),4.91-4.70 (m, 2H), 4.62-4.35 (m, 1H), 4.27-4.08 (m, 3H), 4.05-3.96 (m,1H), 3.60-3.02 (m, 5H), 2.38-2.06 (m, 4H), 2.06-1.97 (m, 1H), 1.37 (d,J=6.0 Hz, 2H), 1.29 (d, J=5.4 Hz, 1H), 0.86 (d, J=8.4 Hz, 2H), 0.65-0.50(m, 2H); MS (ES+) m/z 635.1 (M+1).

Example 226 Synthesis of(4S,5R)-3-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)-piperidin-4-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid Step 1. Preparation of methyl(4I,5R)-3-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate

Following the procedure as described in Example 223. Step 2 and makingnon-critical variations as required to replace4-((4-(chlorocarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-1-(2,6-dichlorobenzyl)piperidin-1-iumtrifluoroacetate with5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoylchloride, the title compound was obtained that used directly in the nextstep without any analytical characterization.

Step 2. Preparation of(4S,5R)-3-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(4S,5R)-3-(5-cyclopropyl-4-((1-(1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl)piperidin-4-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylateand following the residue was purified by reverse phase HPLC, the tilecompound was obtained as a colorless solid (0.025 g, 15%): ¹H NMR (300MHz, DMSO-d₆) δ 7.67 (t, J=1.8 Hz, 1H), 7.41 (d, J=1.5 Hz, 2H),6.90-6.75 (m, 2H), 4.85-4.63 (m, 3H), 4.25-3.96 (m, 2H), 3.91-3.77 (m,2H), 3.95-2.89 (m, 2H), 2.26 (m, J=10.8 Hz, 2H), 2.09-1.87 (m, 2H),1.87-1.57 (m, 3H), 1.38-1.25 (m, 4H), 0.88-0.75 (m, 2H), 0.49-0.62 (m,2H); Note: COOH proton not observed; MS (ES+) m/z 633.2, 635.1 (M+1).

Example 227 Synthesis of(4S,5R)-3-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid Step 1. Preparation of4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropropyl-2-fluorobenzoylchloride

Following the procedure as described in Example 224. Step 1 and makingnon-critical variations as required to replace4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)-4-fluoropiperidin-4-yl)methoxy)-5-cyclopropropyl-2-fluorobenzoicacid with4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoicacid, the title compound was used without further purification.

Step 2. Preparation of methyl(4S,5R)-3-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)-benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate

Following the procedure as described in Example 223, Step 2 and makingnon-critical variations as required to replace4-((4-(chlorocarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-1-(2,6-dichlorobenzyl)piperidin-1-iumtrifluoroacetate with4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoylchloride, the title compound was obtained as pale yellow oil (0.24 g,86%): MS (ES+) m/z 631.0, 633.0 (M+1).

Step 3. Preparation of(4S,5R)-3-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(4S,5R)-3-(4-((1-(3-chloro-2-fluoro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate,the title compound was obtained as colorless solid (83%, 0.17 g): ¹H NMR(300 MHz, CDCl₃) δ 12.6 (br s, 1H), 8.35-8.05 (m, 2H), 6.98-6.70 (m,2H), 4.88-4.74 (m, 2H), 4.55-4.20 (br s, 1H), 4.25-4.07 (m, 1H),4.04-4.00 (m, 1H), 3.97-3.82 (m, 2H), 3.55-3.17 (m, 4H), 3.10-2.85 (m,1H), 2.12-1.85 (m, 4H), 1.80-1.51 (m, 2H), 1.37 (d, =6.0 Hz, 2H), 1.29(d, J 5.7 Hz, 1H), 0.85 (d, J=8.1 Hz, 2H), 0.65-0.50 (m, 2H): MS (ES+)m/z 617.1, 619.1 (M+1).

Example 228 Synthesis of (4S.S,5R)-3-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid Step 1. Preparation of methyl(4S,5R)-3-(4-(benzyloxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate

Following the procedure as described in Example 223, Step 2 and makingnon-critical variations as required to replace4-((4-(chlorocarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-1-(2,6-dichlorobenzyl)piperidin-1-iumtrifluoroacetate with 4-(benzyloxy)-5-cyclopropyl-2-fluorobenzoylchloride, the title compound was obtained as pale yellow oil (0.28 g,50% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.44-7.34 (m, 5H), 7.04 (d, J=7.8Hz, 1H), 6.60 (d, J=11.9 Hz, 1H), 5.10 (s, 2H), 4.93 (m, 1H), 4.34 (d,J=7.6 Hz, 1H), 4.23-4.01 (m, 1H), 3.79 (s, 2H), 2.09 (m, 1H), 1.58 (s,1H), 1.50 (d, J=6.0 Hz, 3H), 1.39-132 (m, 1H), 0.90 (d, J=8.5 Hz; 2H),0.68-0.58 (m, 2H); MS (ES+) m/z 414.2 (M+1)

Step 2. Preparation of methyl(4S,5R)-3-(5-cyclopropyl-2-fluoro-4-hydroxybenzoyl)-5-methyloxazolidine-4-carboxylate

To a solution of methyl(4S,5R)-3-(4-(benzyloxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate(0.41 g, 0.69 mmol) in anhydrous methanol (4.5 mL) was added wettedpalladium on charcoal (0.15 g). The flask was fitted with an atmosphereof hydrogen and stirred for 4 h. The reaction mixture was filtered overCelite and the filter pad was washed with ethyl acetate (50 mL). Thefiltrate was concentrated in vacuo to afford the title compound ascolorless solid (0.26 g, quantitative yield): MS (ES+) m/z 324.2 (M+1).

Step 3. Preparation of methyl(4S,5R)-3-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate

To a solution of methyl(4S,5R)-3-(5-cyclopropyl-2-fluoro-4-hydroxybenzoyl)-5-methyloxazolidine-4-carboxylate(0.26 g, 0.69 mmol) in N,N-dimethylformamide (5.0 mL) was added cesiumcarbonate (0.34 g, 1.04 mmol) and tert-butyl4-((tosyloxy)methyl)piperidine-1-carboxylate (0.38 g, 1.04 mmol). Thereaction mixture was heated to 75° C. for 8 h, after which it wasdiluted saturated ammonium chloride (50 mL) and extracted with ethylacetate (3×50 mL). The combined organic extracts were washed with 5%lithium chloride (50 mL) and then dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The resulting residue waspurified by column chromatography to afford the title compound ascolorless solid (0.26 g, 71% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.02 (d,J=7.8 Hz, 1H), 6.50 (d, J=11.9 Hz, 1H), 4.92 (dd, J=19.4, 4.6 Hz, 2H),4.33 (d, J=7.7 Hz, 1H), 4.20-4.11 (m, 3H), 3.85-3.70 (m, 4H), 2.74 (t,J=11.9 Hz, 2H), 2.04-1.95 (m, 2H), 1.90-1.77 (m, 2H), 1.48 (d, J=6.0 Hz,3H), 1.44 (s, 9H), 1.36-1.15 (m, 3H), 0.87 (m, 2H), 0.64-0.56 (m, 2H),

Step 4. Preparation of4-((2-cyclopropyl-5-fluoro-4-((4S,5R)-4-(methoxycarbonyl)-5-methyloxazolidine-3-carbonyl)henoxy)methyl)piperidin-1-ium trifluoroacetate

To a solution of methyl(4S,5R)-3-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate(0.12 g, 0.23 mmol) in dichloromethane (2.3 mL) was addedtrifluoroacetic acid (0.18 mL). The solution was stirred overnight, andthe evaporated in vacuo to afford the title compound, which was useddirectly for the next step without further purification.

Step 5. Preparation of methyl(4S,5R)-3-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate

To a solution of4-((2-cyclopropyl-5-fluoro-4-((4S,5R)-4-(methoxycarbonyl)-5-methyloxazolidine-3-carbonyl)phenoxy)methyl)piperidin-1-iumtrifluoroacetate (0.23 mmol) in N,N-dimethylformamide (2.3 mL) was addedcesium carbonate (0.35 g, 1.06 mmol) and2-chloro-5-(trifluoromethyl)benzyl methanesulfonate (0.11 g, 0.37 mmol).The reaction mixture was stirred at 85° C. for 3 h, diluted withsaturated sodium bicarbonate (40 mL), and then extracted with ethylacetate (3×40 mL). The combined organic extracts were washed with 5%lithium chloride (40 mL) and then dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The resulting residue waspurified by column chromatography to afford the title compound as a paleyellow oil (0.091 g, 65%): MS (ES+) m/z 613.2, 615.3 (M+1).

Step 6. Preparation of(4S,5R)-3-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(4S,5R)-3-(4-((1-(2-chloro-5-(trifluoromethyl)benzyl)piperidin-4-yl)methoxy)-5-cyclopropyl-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate,the title compound was obtained as a colorless solid (0.022 g, 24%): ¹HNMR (300 MHz, CDCl₃) δ 7.79 (s, 1H), 7.70-7.55 (m, 2H), 6.97-6.70 (m,2H), 4.79 (s, 2H), 4.25-4.01 (m, 1H), 4.00-3.90 (m, 2H), 3.89 (s, 2H),2.88-2.79 (m, 2H), 2.10 (t, J 11.4 Hz, 2H), 1.85-1.70 (m, 3H), 1.40-1.28(m, 4H), 1.28-1.23 (m, 1H), 1.37 (t, J=6.2 Hz, 2H), 0.82-0.75 (m, 2H),0.65-0.48 (m, 2H); MS (ES+) m/z 599.2, 601.2 (M+1); Note: COOH protonnot observed.

Example 229 Synthesis of(4S,5R)-3-(5-cyclopropyl-4-((1-((R)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylicacid Step 1. Preparation of methyl(40,5R)-3-(5-cyclopropyl-4-((1-((R)-(3,5-dichlorophenyl)-(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate

Following the procedure as described in Example 223, Step 2 and makingnon-critical variations as required to replace4-((4-(chlorocarbonyl)-2-cyclopropyl-5-fluorophenoxy)methyl)-1-(2,6-dichlorobenzyl)piperidin-1-iumtrifluoroacetate with(R)-5-cyclopropyl-4-((1-((3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoylchloride, the title compound was obtained that was used in the next stepwithout any further analytical characterization.

Step 2. Preparation of(4S,5R)-3-(5-cyclopropyl-4-((1-((R)-(3,5-dichlorophenyl)(phenyl)-methyl)-3-methylazetidin-3-yl)m)-5-methyloxazolidine-4-carboxylicacid

Following the procedure as described in Example 33, Step 2 and makingnon-critical variations as required to replace (S)-methyl1-(4-(2-(1-(1-(tert-butoxycarbonyl)azetidin-3-yl)-1H-pyrazol-5-yl-4-chlorophenoxy)-2,5-difluorobenzoyl)pyrrolidine-2-carboxylatewith methyl(4S,5R)-3-(5-cyclopropyl-4-((1-((R)-(3,5-dichlorophenyl)(phenyl)methyl)-3-methylazetidin-3-yl)methoxy)-2-fluorobenzoyl)-5-methyloxazolidine-4-carboxylate,the tile compound was obtained as a colorless solid (0.043 g, 76%): ¹HNMR (300 MHz, CDCl₃) δ 12.59 (br s, 1H), 7.90-7.56 (m, 2H), 7.56-7.15(m, 6H), 7.02-6.77 (m, 2H), 4.81 (s, 1H), 4.28-3.75 (m, 5H), 2.83 (br s,1H), 2.2-1.85 (m, 1H), 1.62-1.05 (m, 8H), 0.904-0.70 (m, 2H), 0.60-0.45(m, 2H): MS (ES+) m/z 627.2, 629.2 (M+1). Note: 2H proton signal isunderneath water signal (8=3.12 ppm).

Example 230 Synthesis of(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of methyl(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylateand methyl(2S,3S,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate

To a solution of methyl(2S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-3-methyl-4-oxopyrrolidine-2-carboxylate(0.25 g, 0.51 mmol) in tetrahydrofuran (5.0 mL) cooled to −78° C. wasadded(S)-3,3-diphenyl-1-methyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole(0.55 mL, 0.51 mmol), followed by the dropwise addition of boranedimethylsulfide complex (0.05 mL, 0.52 mmol). The reaction mixture wasstirred at −78° C. for 0.5 h, warmed to ambient temperature for 0.5 hand quenched with the addition of methanol (2.0 mL). After 0.5 h, thereaction mixture was diluted with aqueous hydrochloric acid (50 mL, 0.2mol/L) and extracted with ethyl acetate (3×50 mL). The combined organicextracts were dried over anhydrous magnesium sulfate, filtered,concentrated in vacuo. The residue was purified by column purificationeluting with ethyl acetate in hexanes to afford the two title compounds:first eluent of the title compound as colorless gum (0.11 g, 46%) andthe second eluent of the title compound as a colorless solid (0.13 g,51%); MS (ES+) m/z 486.3 (M+1).

Step 2. Preparation of(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylicacid

To a solution of methyl(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate(0.11 g, 0.24 mmol) in tetrahydrofuran (6.0 mL) and water (3.0 mL) wasadded potassium carbonate (0.43 g, 3.11 mmol). The reaction mixture wasfitted with a condenser, and stirred at reflux for 16 h, after which itwas diluted with aqueous hydrochloric acid (1 mol/L, 50 mL), andextracted with ethyl acetate (4×50 mL). The combined organic extractswere dried over anhydrous magnesium sulfate, filtered, and concentratedin vacuo. The residue was purified by preparatory HPLC (acetonitrile andwater) to afford the title compound as a colorless solid (0.03 g, 27%yield): ¹H NMR (300 MHz, CDCl₃) δ 6.96 (d, J=7.4 Hz, 1H), 6.50 (d,J=11.8 Hz, 1H), 4.15-3.92 (m, 2H), 3.80-3.65 (m, 1H), 3.48-3.35 (m, 3H),2.61 (br s, 1H), 2.01 (s, 4H), 1.81-1.60 (m, 12H), 1.14 (d, J=5.9 Hz,3H), 0.90-0.80 (m, 2H), 0.61 (d, J=3.0 Hz, 2H); Note: COOH and OHprotons not observed: MS (ES+) m/z 472.3 (M+1).

Example 231 Synthesis of(2S,3S,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylicacid Step 1. Preparation of(2S,3S,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylicacid

Following the procedure as described in Example 230, Step 2 and makingnon-critical variations as required to replace methyl(2S,3R,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylatewith methyl(2S,3S,4S)-1-(4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoyl)-4-hydroxy-3-methylpyrrolidine-2-carboxylate,title compound was obtained as a colorless solid (0.061 g, 50%): ¹H NMR(300 MHz, CDCl₃) δ 7.00 (d, J=7.8 Hz, 1H), 6.48 (d, J=12.0 Hz, 1H), 4.52(d, J=8.8 Hz, 1H), 4.06 (s, 1H), 3.85-3.70 (m, 1H), 3.58-3.42 (m, 3H),2.54 (br s, 1H), 2.11-1.95 (m, 4H), 1.75-1.62 (m, 12H), 1.15 (d, J=6.6Hz, 3H), 0.84 (d, J=8.3 Hz, 2H), 0.65-0.55 (m, 2H); Note: COOH and OHprotons not observed; MS (ES+) m/z 472.3.

Example 232 Electrophysiological Assay (EP) (In Vitro Assay)

Patch voltage clamp electrophysiology allows for the direct measurementand quantification of block of voltage-gated sodium channels (NaV's),and allows the determination of the time- and voltage-dependence ofblock which has been interpreted as differential binding to the resting,open, and inactivated states of the sodium channel (Hille, B., Journalof General Physiology (1977), 69: 497-515).

The following patch voltage clamp electrophysiology studies wereperformed on representative compounds of the invention using humanembryonic kidney cells (HEK), permanently transfected with an expressionvector containing the full-length cDNA coding for the desired humansodium channel α-subunit, grown in culture media containing 10% FBS, 1%PSG, and 0.5 mg/mL G418 at 37° C. with 5% CO2. HEK cells used for theelectrophysiology (EP) recordings had a passage number of less than 40for all studies and were used within three days from the time ofplating. NaV1.7 and NaV1.5 cDNAs (NM_002977 and AC137587: SCN5A,respectively) were stably expressed in HEK-293 cells. The 31 subunit wascoexpressed in both the NaV1.7 and NaV1.5 cell lines.

Sodium currents were measured using the patch clamp technique in thewhole-cell configuration using either a PatchXpress automated voltageclamp or manually using an Axopatch 200B (Axon Instruments) or Model2400 (A-M systems) amplifier. The manual voltage clamp protocol was asfollows: Borosilicate glass micropipettes were fire-polished to a tipdiameter yielding a resistance of 2-4 Mohms in the working solutions.The pipette was filled with a solution comprised of: 5 mM NaCl, 10 mMCsCl, 120 mM CsF, 0.1 mM CaCl₂), 2 mM MgCl2, 10 mM HEPES, 10 mM EGTA;and adjusted to pH 7.2 with CsOH. The external solution had thefollowing composition: 140 mM NaCl, 5 mM KCl, 2 mM CaCl₂), 1 mM MgCl2,10 mM HEPES; and adjusted to pH 7.4 with NaOH. In some studies, theexternal sodium was reduced by equimolar replacement with choline.Osmolarity in the CsF internal and NaCl external solutions was adjustedto 300 mOsm/kg and 310 mOsm/kg with glucose, respectively. Allrecordings were performed at ambient temperature in a bath chamber witha volume of 150 μL. Control sodium currents were measured in 0.5% DMSO.Controls and representative compounds of the invention were applied tothe recording chamber through a 4-pinch or 8-pinch valve bath perfusionsystem manufactured by ALA Scientific Instruments.

Currents were recorded at 40 kHz sampling frequency, filtered at 5 Hz,and stored using a Digidata-1322A analogue/digital interface with thepClamp software (Axon Instruments). Series resistance compensation wasapplied (60-80%). Cells were rejected if currents showed inadequatevoltage control (as judged by the IV relationship during stepwiseactivation). All statistics in this study are given as mean±SD.

The membrane potential was maintained at a voltage where inactivation ofthe channel is complete (which was −60 mV for both NaV1.7 and NaV1.5).The voltage is then stepped back to a very negative (Vhold=150 mV)voltage for 20 ms and then a test pulse is applied to quantify thecompound block. The 20 ms brief repolarization was long enough forcompound-free channels to completely recover from fast inactivation, butthe compound-bound channels recovered more slowly such that negligiblerecovery could occur during this interval. The percent decrease insodium current following wash-on of compound was taken as the percentblock of sodium channels. Data for representative compounds of formula(I) is provided in Table 1.

Example 233 Tritiated Compound Binding to Membranes Isolated from Cellsthat Heterologously Express hNav1.7 and the β1 Subunit

Preparation of membranes containing recombinantly expressed sodiumchannels: Frozen recombinant cell pellets were thawed on ice and dilutedto 4 times the cell pellet weight with ice cold 50 mM Tris HCl, pH 7.4buffer. The cell suspensions were homogenized on ice using a motorizedglass dounce homogeniser. Homogenates were further diluted 8.4 timeswith ice cold 50 mM Tris HCl, pH 7.4 buffer and then centrifuged at200×g at 4° C. for 15 min. The supernatants were collected andcentrifuged at 10000×g at 4° C. for 50 min. The pellets were thenre-suspended in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer containing 1%v/v protease inhibitors (Calbiochem) and re-homogenized on ice. Thehomogenized membranes were then processed through a syringe equippedwith a 26 gauge needle. Protein concentrations were determined byBradford Assay and the membranes were stored at −80° C.

Radioligand Binding Studies:

Saturation experiments. A representative compound of formula (I) havinga methyl group was tritiated. Three tritiums were incorporated in placeof methyl hydrogens to generate [³H]compound. Binding of thisradioligand was performed in 5 mL borosilicate glass test tubes at roomtemperature. Binding was initiated by adding membranes to increasingconcentrations of [H]compound in 100 mM NaCl, 20 mM Tris HCl, pH 7.4buffer containing 0.01% w/v bovine serum albumin (BSA) for 18 h.Non-specific binding was determined in the presence of 1 μM unlabeledcompound. After 18 h, the reactants were filtered through GF/C glassfiber filters presoaked in 0.5% w/v polyethylene imine. Filters werewashed with 15 mL ice cold 100 mM NaCl, 20 mM Tris HCl, pH7.4 buffercontaining 0.25% BSA to separate bound from free ligand. [³H] compoundbound to filters was quantified by liquid scintillation counting.

Competitive Binding Experiments:

Binding reactions were performed in 96-well polypropylene plates at roomtemperature for 18 h. In 360 μL, membranes were incubated with 100 pM[³H]compound and increasing concentrations of Test Compound.Non-specific binding was defined in the presence of 1 μM unlabeledcompound. Reactions were transferred and filtered through 96-well glassfiber/C filter plates presoaked with 0.5% polyethylene imine. Thefiltered reactions were washed 5 times with 200 μL ice cold buffercontaining 0.25% BSA. Bound radioactivity was determined by liquidscintillation counting.

Data Analysis: For saturation experiments, non-specific binding wassubtracted from total binding to provide specific binding and thesevalues were recalculated in terms of pmol ligand bound per mg protein.Saturation curves were constructed and dissociation constants werecalculated using the single site ligand binding model:Beq=(Bmax*X)/(X+Kd), where Beq is the amount of ligand bound atequilibrium, Bmax is the maximum receptor density, Kd is thedissociation constant for the ligand, and X is the free ligandconcentration. For competition studies percent inhibition was determinedand ICso values were calculated using a 4 parameter logistic model (%inhibition=(A+((B−A)/(1+((x/C){circumflex over ( )}D)))) using XLfit,where A and B are the maximal and minimum inhibition respectively, C isthe ICso concentration and D is the (Hill) slope.

Representative compounds, when tested in this model, demonstratedaffinities as set forth in Table 1.

TABLE 1 LBA Nav1.7 Nav1.5 Example Structure (μM) (μM) (μM)  1

0.0196 0.0135 3.505  2

0.4261  3

0.0089  4

0.8172  5

0.4682  6

3.5794 0.5318 2.1157  7

3.0467  8

1.6922  9

>10  10

0.6809  11

0.2005 0.0361 2.1872  12

0.9836  13

0.1726  14

2.3711  15

6.9628  16

0.0398  17

0.0872  18

4.5009  19

0.4432  20

0.5542  21

0.3594  22

>10  23

3.9606  24

2.7250  25

>10  26

0.0181  27

0.0217  28

0.0176  29

0.6287  30

0.3447  31

>10  32

1.5368  33

>10  34

>10  35

7.8288  36

>10  37

5.2302  38

0.1521  39

0.0436  40

0.452  41

0.6401  42

0.2313  43

0.0823  44

10 30  45

8.4 11.7  46

0.15 0.87  47

10 16  48

0.04 0.64  49

0.01 0.23  50

0.03 0.34 19.41  51

0.1 0.92 14  52

0.098 1.4 7.5  53

0.017 2 14  54

0.058 0.62 9.7  55

0.25 0.79 29  56

0.41 1.8 30  57

0.43 2.1 23  58

0.083 0.63 21  59

0.034 0.55 26  60

0.34 1.9 13  61

0.97 2.7 12  62

0.16 1.1 28  63

0.17 0.98 18  64

0.06 0.79 8.5  65

10 5.3 23  66

0.07 0.8 8.1  67

1 3 7.5  68

0.1 0.52 19  69

0.17 0.52 30  70

0.31 1.6 30  71

6.1 11 30  72

3.6 5.6 24  73a

0.36 2.2 12  73b

0.093 1.5 22  74

0.024 0.7 7.5  75

0.6 1.3 25  76

0.087 1 17  77

7.4 11 12  78

0.0094 0.087 13  79a

0.047 0.69 30  79b

0.073 0.79 30  80

0.59 1.5 30  81

8.9 16 30  82

1.1 1.8 30  83

0.48 2 14  84

10 17 30  85

0.59 1.1 17  86

1.6 1.9 26  87

0.056 1.3 7.1  88

0.43 7 8.2  89

0.13 0.79 17  90

0.021 0.16 13  91

0.015 0.3 23  92

0.016 0.31 11  93

0.081 0.66 30  94

0.1 0.6 30  95

10 30 30  96

0.38 1.5 30  97

0.44 0.57 30  98

0.44 0.74 30  99

0.23 0.55 30 100

0.031 0.44 18 101

0.066 0.52 30 102

0.065 0.33 23 103

0.033 0.34 30 104

0.13 1.6 30 105

0.037 0.22 22 106

0.027 0.13 21 107

0.039 0.73 12 108

0.017 0.22 9.6 109

0.051 0.89 30 110

0.37 10 10 111

0.036 0.23 14 112

0.52 2 30 113

0.076 0.61 15 114

0.02 1.7 13 115

0.0077 0.3 11 116

0.012 0.58 15 117

0.023 0.51 8.5 118

0.021 0.76 15 119

0.015 0.85 9.4 120

0.027 0.29 14 121a

0.02 0.88 13 121b

0.018 0.88 17 122

0.43 2 30 123a

0.048 0.49 7.1 123b

0.031 0.41 7.7 124

0.4 1.5 12 125

0.016 0.38 6.2 126a

0.12 2.3 10 126b

0.1 1.4 10 127

0.12 0.4 13 128

0.087 0.71 30 129

0.022 0.16 9.4 130

0.027 0.16 14 131

0.028 0.25 18 132a

0.024 0.33 17 132b

0.024 0.43 30 133

1.4 18 9.4 134

0.072 0.63 7.1 135

0.39 2.6 30 136

0.11 1.1 30 137a

0.57 3.7 15 137b

0.31 2.4 30 138a

0.0069 0.3 13 138b

0.0076 0.32 11 139a

0.65 5 25 139b

0.8 7.1 22 140a

0.014 0.17 2.7 140b

0.021 0.16 3.7 141

0.49 6.1 30 142a

0.25 1.5 17 142b

0.76 3 15 143

0.17 1.2 21 144

0.87 3.5 30 145

0.035 0.64 16 146

0.18 1.5 8.4 147

0.26 2.1 14 148

0.049 0.62 17 149

0.01 0.3 17 150

0.085 1.2 19 151

0.058 0.78 5.2 152

0.093 1.3 13 153

0.55 1.1 19 154

0.059 0.83 16 155

0.068 0.9 9.3 156

0.83 3.1 17 157

0.48 2.2 30 158

0.56 1.4 30 159

0.08 1 17 160

0.035 0.64 16 161

0.39 0.98 30 162

0.0073 0.094 5.7 163

0.12 0.82 4.7 164

0.025 0.062 13 165

0.0092 0.02 30 166

0.09 0.75 13 167

0.19 0.66 28 168a

0.61 3.3 6.8 168b

0.18 1.3 8.2 169

0.091 0.78 13 170

0.26 3.8 3.7 171

0.025 0.24 9 172

1 4.2 14 173

0.065 0.33 23 174

0.026 0.34 30 175

0.11 1.2 30 176

0.36 1.3 7.2 177

178

0.19 1.6 11 179

0.4 0.83 30 180

0.83 1.4 30 181

0.05 0.23 30 182

0.032 0.22 25 183

0.031 1.9 9.2 184

0.46 1.3 23 185

0.1 9.6 17 186

0.35 8.3 12 187

3.3 7.3 11 188

9.1 6.6 16 189

0.12 4 15 190

0.19 2.9 30 191

2.7 19 30 192

10 30 30 193

0.02 0.99 7.6 194

0.022 0.64 10 195

1.9 5.9 30 196

0.018 1.4 13 197

0.63 3.9 30 198

1.1 4.5 18 199

0.47 3.6 15 200

0.084 0.79 12 201

10 13 24 202

1.9 4.4 16 203

10 10 19 204

0.56 7.8 23 205

0.17 2.2 25 206

0.26 2.6 16 207

0.036 0.38 16 208

0.082 0.21 16 209

0.2 0.7 20 210a

0.22 1.9 27 210b

0.03 0.81 17 211

2.3 6.7 14 212

0.29 3.5 17 213

5.3 3.4 7.6 214

9.7 8.2 11 215

1.1 5.4 30 216

0.6 8.6 30 217

2.7 19 30 218

0.23 1.6 24 219

0.0064 0.26 12 220

0.16 0.83 30 221

0.5 1.1 16 222

0.013 0.21 30 223

0.91 2.9 3.9 224

0.014 0.1 22 225

226

0.012 0.13 6.1 227

0.029 0.065 16 228

0.017 0.087 25 229

0.0069 0.27 30 230

0.021 0.032 11 231

0.29 0.36 15

Example 234 Analgesia Induced by Sodium Channel Blockers

Heat Induced Tail Flick Latency Test

In this test, the analgesia effect produced by administering a compoundof the invention can be observed through heat-induced tail-flick inmice. The test includes a heat source consisting of a projector lampwith a light beam focused and directed to a point on the tail of a mousebeing tested. The tail-flick latencies, which are assessed prior to drugtreatment, and in response to a noxious heat stimulus, i.e., theresponse time from applying radiant heat on the dorsal surface of thetail to the occurrence of tail flick, are measured and recorded at 40,80, 120, and 160 minutes.

For the first part of this study, 65 animals undergo assessment ofbaseline tail flick latency once a day over two consecutive days. Theseanimals are then randomly assigned to one of the 11 different treatmentgroups including a vehicle control, a morphine control, and 9 compoundsat 30 mg/Kg are administered intramuscularly. Following doseadministration, the animals are closely monitored for signs of toxicityincluding tremor or seizure, hyperactivity, shallow, rapid or depressedbreathing and failure to groom. The optimal incubation time for eachcompound is determined via regression analysis. The analgesic activityof the test compounds is expressed as a percentage of the maximumpossible effect (% MPE) and is calculated using the following formula:

${\%\mspace{14mu}{MPE}} = {\frac{{{Postdrug}\mspace{14mu}{latency}} - {{Predrug}\mspace{14mu}{latency}}}{{{Cut}\text{-}{off}\mspace{14mu}{time}\mspace{14mu}( {10\mspace{14mu} s} )} - {{Predrug}\mspace{14mu}{latency}}} \times 100\%}$where:

Postdrug latency=the latency time for each individual animal takenbefore the tail is removed (flicked) from the heat source afterreceiving drug.

Predrug latency=the latency time for each individual animal taken beforethe tail is flicked from the heat source prior to receiving drug.

Cut-off time (10 s)=is the maximum exposure to the heat source.

Acute Pain (Formalin Test)

The formalin test is used as an animal model of acute pain. In theformalin test, animals are briefly habituated to the plexiglass testchamber on the day prior to experimental day for 20 minutes. On the testday, animals are randomly injected with the test articles. At 30 minutesafter drug administration, 50 μL of 10% formalin is injectedsubcutaneously into the plantar surface of the left hind paw of therats. Video data acquisition begins immediately after formalinadministration, for duration of 90 minutes.

The images are captured using the Actimetrix Limelight software whichstores files under the *.llii extension, and then converts it into theMPEG-4 coding. The videos are then analyzed using behaviour analysissoftware “The Observer 5.1”, (Version 5.0, Noldus InformationTechnology, Wageningen, The Netherlands). The video analysis isconducted by watching the animal behaviour and scoring each according totype, and defining the length of the behaviour (Dubuisson and Dennis,1977). Scored behaviours include: (1) normal behaviour, (2) putting noweight on the paw, (3) raising the paw, (4) licking/biting or scratchingthe paw. Elevation, favoring, or excessive licking, biting andscratching of the injected paw indicate a pain response. Analgesicresponse or protection from compounds is indicated if both paws areresting on the floor with no obvious favoring, excessive licking, bitingor scratching of the injected paw.

Analysis of the formalin test data is done according to two factors: (1)Percent Maximal Potential Inhibitory Effect (% MPIE) and (2) pain score.The % MPIEs is calculated by a series of steps, where the first is tosum the length of non-normal behaviours (behaviours 1,2,3) of eachanimal. A single value for the vehicle group is obtained by averagingall scores within the vehicle treatment group. The following calculationyields the MPIE value for each animal:MPIE (%)=100−[(treatment sum/average vehicle value)×100%]

The pain score is calculated from a weighted scale as described above.The duration of the behaviour is multiplied by the weight (rating of theseverity of the response), and divided by the total length ofobservation to determine a pain rating for each animal. The calculationis represented by the following formula:Pain rating=[0(To)+1(T1)+2(T2)+3(T3)]/(To+T1+T2+T3)

CFA Induced Chronic Inflammatory Pain

In this test, tactile allodynia is assessed with calibrated von Freyfilaments. Following a full week of acclimatization to the vivariumfacility, 150 μL of the “Complete Freund's Adjuvant” (CFA) emulsion (CFAsuspended in an oil/saline (1:1) emulsion at a concentration of 0.5mg/mL) is injected subcutaneously into the plantar surface of the lefthind paw of rats under light isoflurane anaesthesia. Animals are allowedto recover from the anaesthesia and the baseline thermal and mechanicalnociceptive thresholds of all animals are assessed one week after theadministration of CFA. All animals are habituated to the experimentalequipment for 20 minutes on the day prior to the start of theexperiment. The test and control articles are administrated to theanimals, and the nociceptive thresholds measured at defined time pointsafter drug administration to determine the analgesic responses to eachof the six available treatments. The time points used are previouslydetermined to show the highest analgesic effect for each test compound.

Thermal nociceptive thresholds of the animals are assessed using theHargreaves test. Animals are placed in a Plexiglas enclosure set on topof an elevated glass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 30° C. forall test trials. Animals are allowed to accommodate for 20 minutesfollowing placement into the enclosure until all exploration behaviourceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter (IITC,Woodland Hills, Calif.) is used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source are set at 1 and 45 respectively, and a cut off time of 20seconds is employed to prevent tissue damage.

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.) following the Hargreaves test. Animals areplaced in an elevated Plexiglas enclosure set on a mire mesh surface.After 10 minutes of accommodation, pre-calibrated Von Frey hairs areapplied perpendicularly to the plantar surface of both paws of theanimals in an ascending order starting from the 0.1 g hair, withsufficient force to cause slight buckling of the hair against the paw.Testing continues until the hair with the lowest force to induce a rapidflicking of the paw is determined or when the cut off force ofapproximately 20 g is reached. This cut off force is used because itrepresent approximately 10% of the animals' body weight and it serves toprevent raising of the entire limb due to the use of stiffer hairs,which would change the nature of the stimulus.

Postoperative Models of Nociception

In this model, the hypealgesia caused by an intra-planar incision in thepaw is measured by applying increased tactile stimuli to the paw untilthe animal withdraws its paw from the applied stimuli. While animals areanaesthetized under 3.5% isofluorane, which is delivered via a nosecone, a 1 cm longitudinal incision is made using a number 10 scalpelblade in the plantar aspect of the left hind paw through the skin andfascia, starting 0.5 cm from the proximal edge of the heel and extendingtowards the toes. Following the incision, the skin is apposed using 2,3-0 sterilized silk sutures. The injured site is covered with Polysporinand Betadine. Animals are returned to their home cage for overnightrecovery.

The withdrawal thresholds of animals to tactile stimuli for bothoperated (ipsilateral) and unoperated (contralateral) paws can bemeasured using the Model 2290 Electrovonfrey anesthesiometer (IITC LifeScience, Woodland Hills, Calif.). Animals are placed in an elevatedPlexiglas enclosure set on a mire mesh surface. After at least 10minutes of acclimatization, pre-calibrated Von Frey hairs are appliedperpendicularly to the plantar surface of both paws of the animals in anascending order starting from the 10 g hair, with sufficient force tocause slight buckling of the hair against the paw. Testing continuesuntil the hair with the lowest force to induce a rapid flicking of thepaw is determined or when the cut off force of approximately 20 g isreached. This cut off force is used because it represent approximately10% of the animals' body weight and it serves to prevent raising of theentire limb due to the use of stiffer hairs, which would change thenature of the stimulus.

Neuropathic Pain Model; Chronic Constriction Injury

Briefly, an approximately 3 cm incision is made through the skin and thefascia at the mid thigh level of the animals' left hind leg using a no.10 scalpel blade. The left sciatic nerve is exposed via blunt dissectionthrough the biceps femoris with care to minimize haemorrhagia. Fourloose ligatures are tied along the sciatic nerve using 4-0non-degradable sterilized silk sutures at intervals of 1 to 2 mm apart.The tension of the loose ligatures is tight enough to induce slightconstriction of the sciatic nerve when viewed under a dissectionmicroscope at a magnification of 4 fold. In the sham-operated animal,the left sciatic nerve is exposed without further manipulation.Antibacterial ointment is applied directly into the wound, and themuscle is closed using sterilized sutures. Betadine is applied onto themuscle and its surroundings, followed by skin closure with surgicalclips.

The response thresholds of animals to tactile stimuli are measured usingthe Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals are placed in an elevated Plexiglasenclosure set on a mire mesh surface. After 10 minutes of accommodation,pre-calibrated Von Frey hairs are applied perpendicularly to the plantarsurface of both paws of the animals in an ascending order starting fromthe 0.1 g hair, with sufficient force to cause slight buckling of thehair against the paw. Testing continues until the hair with the lowestforce to induce a rapid flicking of the paw is determined or when thecut off force of approximately 20 g is reached. This cut off force isused because it represents approximately 10% of the animals' body weightand it serves to prevent raising of the entire limb due to the use ofstiffer hairs, which would change the nature of the stimulus.

Thermal nociceptive thresholds of the animals are assessed using theHargreaves test. Following the measurement of tactile thresholds,animals are placed in a Plexiglass enclosure set on top of an elevatedglass platform with heating units. The glass platform isthermostatically controlled at a temperature of approximately 24 to 26°C. for all test trials. Animals are allowed to accommodate for 10minutes following placement into the enclosure until all explorationbehaviour ceases. The Model 226 Plantar/Tail Stimulator Analgesia Meter(IITC, Woodland Hills, Calif.) is used to apply a radiant heat beam fromunderneath the glass platform to the plantar surface of the hind paws.During all test trials, the idle intensity and active intensity of theheat source are set at 1 and 55 respectively, and a cut off time of 20seconds is used to prevent tissue damage.

Neuropathic Pain Model: Spinal Nerve Ligation

The spinal nerve ligation (SNL) neuropathic pain model is used as ananimal (i.e. rat) model of neuropathic pain. In the SNL test, the lumbarroots of spinal nerves L5 and L6 are tightly ligated to cause nerveinjury, which results in the development of mechanical hyperalgesia,mechanical allodynia and thermal hypersensitivity. The surgery isperformed two weeks before the test day in order for the pain state tofully develop in the animals. Several spinal nerve ligation variationsare used to characterize the analgesic properties of a compound of theinvention.

Ligation of the L5 spinal nerve;

Ligation of the L5 and L6 spinal nerves:

Ligation and transection of the L5 spinal nerve;

Ligation and transection of the L5 and L6 spinal nerves; or

Mild irritation of the L4 spinal nerve in combination with any one ofthe above (1)-(4).

While the animals are anaesthetized under 3.5% isofluorane delivered viaa nose cone, an approximately 2.5 cm longitudinal incision is made usinga number 10 scalpel blade in the skin just lateral to the dorsalmidline, using the level of the posterior iliac crests as the midpointof the incision. Following the incision, the isoflourane is readjustedto maintenance levels (1.5%-2.5%). At mid-sacral region, an incision ismade with the scalpel blade, sliding the blade along the side of thevertebral column (in the saggital plane) until the blade hits thesacrum. Scissors tips are introduced through the incision and the muscleand ligaments are removed from the spine to expose 2-3 cm of thevertebral column. The muscle and fascia are cleared from the spinalvertebra in order to locate the point where the nerve exits from thevertebra. A small glass hook is placed medial to the spinal nerves andthe spinal nerves are gently elevated from the surrounding tissues. Oncethe spinal nerves have been isolated, a small length of non-degradable6-0 sterilized silk thread is wound twice around the ball at the tip ofthe glass hook and passed back under the nerve. The spinal nerves arethen firmly ligated by tying a knot, ensuring that the nerve bulges onboth sides of the ligature. The procedure may be repeated as needed. Insome animals, the L4 spinal nerve may be lightly rubbed (up to 20 times)with the small glass hook to maximize the development of neuropathicpain. Antibacterial ointment is applied directly into the incision, andthe muscle is closed using sterilized sutures. Betadine is applied ontothe muscle and its surroundings, followed by skin closure with surgicalstaples or sterile non-absorable monofilament 5-0 nylon sutures.

The analgesic effect produced by topical administration of a compound ofthe invention to the animals can then be observed by measuring the pawwithdrawal threshold of animals to mechanical tactile stimuli. These maybe measured using either the mechanical allodynia procedure or themechanical hyperalgesia procedure as described below. Afterestablishment of the appropriate baseline measurements by either method,topical formulation of a compound of the invention is applied on theipsilateral ankle and foot. The animals are then placed in plastictunnels for 15 minutes to prevent them from licking the treated area andremoving the compound. Animals are placed in the acrylic enclosure for15 minutes before testing the ipsilateral paw by either of the methodsdescribed below, and the responses are recorded at 0.5, 1.0 and 2.0 hourpost treatment.

A. Mechanical Allodynia Method

The pain threshold of animals to mechanical alloydnia for both operatedand control animals can be measured approximately 14 days post-surgeryusing manual calibrated von Frey filaments as follows. Animals areplaced in an elevated plexiglass enclosure set on a mire mesh surface.Animals are allowed to acclimate for 20-30 minutes. Pre-calibrated VonFrey hairs are applied perpendicularly to the plantar surface of theipsilateral paw of the animals starting from the 2.0 g hair, withsufficient force to cause slight buckling of the hair against the paw toestablish the baseline measurements. Stimuli are presented in aconsecutive manner, either in an ascending or descending order until thefirst change in response is noted, after which four additional responsesare recorded for a total of six responses. The six responses measured ingrams are entered into a formula as described by Chaplan. S. R. et al.,J. Neurosci. Methods, 1994 July; 53(1):55-63, and a 50% withdrawalthreshold is calculated. This constitutes the mechanical allodyniavalue.

B. Mechanical Hyperalgesia Method

The response thresholds of animals to tactile stimuli were measuredusing the Model 2290 Electrovonfrey anesthesiometer (IITC Life Science,Woodland Hills, Calif.). Animals were placed in an elevated Plexiglasenclosure set on a wire mesh surface. After 15 minutes of accommodationin this enclosure, a von Frey hair was applied perpendicularly to theplantar surface of the ipsilateral hind paws of the animals, withsufficient force, measured in grams, to elicit a crisp response of thepaw. The response indicated a withdrawal from the painful stimulus andconstituted the efficacy endpoint. The data were expressed as percentchange from baseline threshold measured in grams.

Example 235 In Vivo Assay for Treatment of Pruritis

The compounds of the invention can be evaluated for their activity asantipruritic agents by in vivo test using rodent models. One establishedmodel for peripherally elicited pruritus is through the injection ofserotonin into the rostral back area (neck) in hairless rats. Prior toserotonin injections (e.g., 2 mg/mL, 50 μL), a dose of a compound of thepresent invention can be applied systemically through oral, intravenousor intraperitoneal routes or topically to a circular area fixed diameter(e.g. 18 mm). Following dosing, the serotonin injections are given inthe area of the topical dosing. After serotonin injection the animalbehaviour is monitored by video recording for 20 min-1.5 h, and thenumber of scratches in this time compared to vehicle treated animals.Thus, application of a compound of the current invention could suppressserotonin-induced scratching in rats.

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon patent publications referred to in this specification areincorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

We claim:
 1. A method of treating pain, comprising administering to amammal in need thereof a therapeutically effective amount of a compoundof Formula (I):

or a pharmaceutically acceptable salt thereof; wherein: the group

in Formula I is selected from the group consisting of:

the group

is selected from the group consisting of:

R³ is selected from the group consisting of hydrogen, F, Cl, Br, I, —CN,C₁₋₈ alkyl and C₁₋₈ haloalkyl; R⁵ is selected from the group consistingof F, Cl, Br, I, —CN, C₁₋₈alkyl, C₁₋₈ haloalkyl, C₁₋₈ alkoxy, C₃₋₈cycloalkyl and C₂₋₇ heterocyclyl, wherein said C₃₋₈ cycloalkyl and C₂₋₇heterocyclyl is optionally substituted with 1-3 substituents selectedfrom F, Cl, Br, I, —OH, —NH₂, —NH(C₁₋₄ alkyl)-, —N(C₁₋₄ dialkyl)-, andC₁₋₄ alkyl substituted with 1-3 substituents selected from F, Cl, Br, I,—OH, —NH₂, —NH(C₁₋₄ alkyl)- and —N(C₁₋₄ dialkyl)-; L is C₁₋₆ alkylene,wherein L is optionally substituted with from 1 to 3 substituentsselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halo, oxo(═O), and C₁₋₄ haloalkyl, and wherein any two substituents attached tothe same atom on L are optionally combined to form a 3- to 5-memberedcarbocyclic ring; the subscript m represents the integer 0 or 1; and X¹and X² are each independently selected from the group consisting ofabsent, —S—, —O— and —N(R^(X))— wherein R^(x) is H, C₁₋₈ alkyl, or C₁₋₈haloalkyl, wherein if the subscript m is 0 then one of X¹ or X² isabsent.
 2. The method of claim 1, wherein R³ is F or Cl; and R⁵ isselected from the group consisting of F, Cl, C₁₋₄ alkyl, C₁₋₄ alkoxy,and C₃₋₈ cycloalkyl.
 3. The method of claim 1, wherein R³ is F or Cl andR⁵ is selected from the group consisting of F, Cl, cyclopropyl,cyclobutyl, and cyclopentyl.
 4. The method of claim 1, wherein X¹ is —O—or —N(H)—; X² is absent; the subscript m is 1; and -(L)- is anoptionally substituted C₁₋₄ alkylene.
 5. The method of claim 1, whereinX¹ is —O— or —N(H)—; X² is absent; the subscript m is 1; and -(L)- isselected from the group consisting of —CH₂—, —C(═O)—, —C(H)(CH₃)—,—CH₂—CH₂—, —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—,—CH₂—C(H)CH₃)—CH₂—, or —CH₂CH₂CH₂CH₂—.
 6. The method of claim 1, whereinX¹ is —O—; the subscript m is 1 and -(L)- is —CH₂—, —C(H)(CH₃)—, or—CH₂—CH₂—.
 7. The method of claim 1, wherein X¹ is absent; X² is —O— or—N(H)—; the subscript m is 1; and -(L)- is selected from the groupconsisting of —CH₂—, —C(═O)—, —C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—,—C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—, —CH₂—C(H)(CH₃)—CH₂—, or —CH₂CH₂CH₂CH₂—.8. The method of claim 1, wherein X¹ and X² are absent; the subscript mis 1; and -(L)- is selected from the group consisting of —CH₂—, —C(═O)—,—C(H)(CH₃)—, —CH₂—CH₂—, —CH₂—C(H)(CH₃)—, —C(H)(CH₃)—C(H₂)—, —CH₂CH₂CH₂—,—CH₂—C(H)(CH₃)—CH₂—, or —CH₂CH₂CH₂CH₂—.
 9. The method of claim 1,wherein X¹ and X² are absent: the subscript m is 1; and -(L)- isselected from the group consisting of —CH₂—, —C(═O)—, —C(H)(CH₃)—, and—CH₂—CH₂—.
 10. The method of claim 1, wherein m is 0; X¹ is selectedfrom —O— and —N(H)—; and X² is absent.
 11. A method of treating pain,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 12. A method of treatingpain, comprising administering to a mammal in need thereof atherapeutically effective amount of a compound selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 13. The method of claim1, wherein the compound or pharmaceutically acceptable salt is:

or a pharmaceutically acceptable salt thereof.